Cross was born in Atlanta, Georgia, the son of Barry and Susi, the former of whom emigrated from Leeds, England. Six months after his birth, Cross' family moved to Florida. After additional moves to New York and Connecticut, the family settled back in Roswell, Georgia, where Cross remained for nearly a decade. His family was poor and Barry left the family when Cross was 10 years old; the two have not spoken since he was 19, though they both primarily resided in New York City until Cross sold his home there in 2011. Cross and his family were evicted from their home while living in Georgia. He spent some time living in motels and at friends' homes while growing up. He has two sisters and once bailed his youngest sibling out of jail.
At age 17, Cross began performing stand-up comedy. The day after he graduated from Northside High School in Atlanta, Cross relocated to New York City. Lacking a plan, he drifted, working briefly for a lawn care company on Long Island. Later, he enrolled at Emerson College in Boston. He would drop out after only a semester, but during his time there, Cross joined This is Pathetic, a college sketch group, where he met John Ennis. In the summer of 1985, the two aspiring actors took a road trip to Los Angeles, although this did not significantly further their acting careers. In Boston, Cross began to perform stand-up more regularly. From the mid-1980s to the early 1990s, Boston had a booming comedy scene, although Cross did not fit the types of acts being booked most of the time. He recalls that it was "a loud-, dumb-, pandering-, racist-, homophobic-type scene".
In 1990, a new comedy scene began to emerge at the famous comedy club chain called Catch a Rising Star (where many of the comedians of the 1970s and 1980s got their start). Alongside Janeane Garofalo, Louis C.K., and other comics, Cross appeared regularly several nights a week. Cross formed the sketch comedy group "Cross Comedy" with 12 other performers, and they put on a new show every week. They were known for playing tricks on the audience, such as introducing fake comics or planting fake hecklers. Cross became increasingly focused on his comedy work. Cross performed at the alternative comedy club Un-Cabaret in Los Angeles.
Radio artist Joe Frank heard David Cross at Un-Cabaret in Los Angeles, and hired him to appear in Frank's 1994 radio programs, "A Hearing" and "The Last Run" which in 1997 was combined to become "The OJ Chronicles" where David appears as OJ's Valet. Cross also starred in the Joe Frank program Jam, produced in 1999 and has more recently worked with Joe Frank on radio shows for KCRW's Unfictional.
Cross' stand-up comedy blends political commentary and satire. In 1999, he performed a one-hour comedy special, The Pride Is Back, on HBO. He has released three recordings: Shut Up You Fucking Baby!, It's Not Funny, and Bigger and Blackerer. Cross' stand up material was featured in Comedy Central's animated series Shorties Watchin' Shorties. In 2004, Shut Up You Fucking Baby! was nominated for the Grammy Award for Best Comedy Album. In 2003, he released his first tour film Let America Laugh and was named #85 on Comedy Central's list of the 100 greatest stand-ups of all time. He appears on Un-Cabaret compilation albums, including Freak Weather Feels Different and The Good, the Bad and the Drugly.
Cross began his professional television career as a writer on The Ben Stiller Show. The series hired him toward the end of its run, and he occasionally made brief appearances in the sketches. He had a speaking role in "The Legend of T.J. O'Pootertoot", a sketch written almost entirely by Cross. It was during this period that he first met Bob Odenkirk, with whom he would later co-create the HBO sketch comedy series Mr. Show in 1995. Cross won an Emmy for his work on The Ben Stiller Show in 1993.
He later co-starred as Tobias Fünke in Arrested Development, which was originally intended to be only a minor role. He has also played smaller roles on programs such as Just Shoot Me!, The Drew Carey Show, NewsRadio, Strangers with Candy, Tim and Eric Awesome Show, Great Job, and Aqua Teen Hunger Force. From October 2005, Cross regularly appeared on Comedy Central's The Colbert Report as Stephen Colbert's nemesis Russ Lieber, a fictional liberal radio talk show host from Madison, Wisconsin. Cross also developed an animated series for Comedy Central called Freak Show, which co-starred H. Jon Benjamin and was cancelled due to low ratings. He has appeared several times on Wonder Showzen.
Cross teamed up with Mr. Show director and producer Troy Miller and Odenkirk to produce a feature film Run Ronnie Run, based on one of their Mr. Show characters. The film satirized the reality television craze, and featured cameos from many stars; however, Odenkirk got into conflict with the studio New Line Cinema, and they then released it direct-to-video. In 1994 and again in 1999, Cross was a guest voice actor on Joe Frank's radio show, featured in the episodes "The Last Run", "A Hearing", "The O.J. Chronicles", and "Jam". In 2013, he returned, making an appearance in an episode of Frank's radio show, entitled "A Conversation."
In 2004, Cross provided voices for a Marine in Halo 2 and a store clerk named Zero in Grand Theft Auto: San Andreas. He was also the voice of the "Happy-Time Harry" doll and Bert Banana in Aqua Teen Hunger Force (although the part was credited as Sir Willups Brightslymoore). Cross has made guest appearances in Tim and Eric Awesome Show, Great Job!. He directed the music video for The Black Keys' song "10 A.M. Automatic," a spoof of public-access television. Paste Magazine ranked it number 24 on their list of the 50 Best Music Videos of the Decade (2000–2009).
Cross appeared in The Strokes' music video for "Juicebox" as a bad local "morning zoo" radio DJ. He also appeared in the New Pornographers' video for "Use It," in Superchunk's video for "Watery Hands" (along with Janeane Garofalo), and in Yo La Tengo's video for "Sugarcube" (along with Bob Odenkirk and John Ennis). Cross contributes to Vice magazine, writing a column, My America.
In 2005, he contributed to the UNICEF benefit song "Do They Know It's Hallowe'en?" and appeared in one of PETA's "I'd Rather Go Naked Than Wear Fur" campaigns.
In the Beastie Boys' 2006 concert film Awesome; I Fuckin' Shot That!, Cross portrays Nathaniel Hörnblowér in the fictional segment "A Day in the Life of Nathaniel Hörnblowér." In I'm Not There, Cross portrays Allen Ginsberg. Both Bill Lawrence and Zach Braff of the TV series Scrubs were eager to have Cross make a cameo appearance on the series as Tobias Fünke, but due to the series' cancellation, the plan never came to fruition.
Cross provided commentary on the Vicarious music video DVD for Tool. He has previously performed comedy as an opening act for the band and its members appeared on Mr. Show several times. He portrayed Ian Hawke in Alvin and the Chipmunks, Alvin and the Chipmunks: The Squeakquel, and Alvin and the Chipmunks: Chipwrecked and voiced Crane in the Kung Fu Panda film franchise.
He starred in David's Situation, a pilot for HBO. It filmed in May 2008 and included many Mr. Show alumni at the taping. On August 6, 2008, Bob Odenkirk announced on bobanddavid.com that David's Situation would not be produced.
Cross' black comedy series The Increasingly Poor Decisions of Todd Margaret, in which he stars and co-writes with Shaun Pye, has run on Channel 4 in the United Kingdom and IFC in the United States since October 2010.
In 2009, Cross released his first book I Drink for a Reason. The book features memoirs, satirical fictional memoirs, and material from Cross that originally appeared in other publications.
In September 2009, Cross performed at his own comedy stage at the ATP New York 2009 music festival, for which he picked Eugene Mirman, H. Jon Benjamin, Jon Glaser, and Derrick Brown & The Navy Gravy to join him. In the same year, Cross and Benjamin created and wrote for Paid Programming on Adult Swim. Paid Programming was not picked up for a full series and Benjamin referred to it as an "abject failure".
On March 29, 2010, his first comedy special in six years, Bigger and Blackerer, was streamed on Epix HD. A CD with "slightly different content" was released on May 25, 2010.
Cross starred alongside Julia Stiles and America Ferrera in It's a Disaster, which premiered at the 2012 Los Angeles Film Festival. Oscilloscope Laboratories has acquired the US distribution rights to the film and plans to release it in select theaters, which started on April 13, 2013.
His directorial debut film Hits premiered at 2014 Sundance Film Festival. Instead of selling the film rights to distributors, Cross instead opted to sell the movie over Bit Torrent through their "bundles" program, which BitTorrent launched to help "legitimize" the platform. According to The Verge it is the first feature film to be distributed in such a format. At the same time Cross launched a Kickstarter campaign for the movie's general release which would then distribute the movie using a pay what you want methodology.
In April 2015, episodes were ordered for a new sketch comedy show starring Cross and Odenkirk called W/ Bob & David. It premiered in November 2015 on Netflix. Cross and Odenkirk write, star in, and produce the show.
Cross announced that he would embark on a 51-date nationwide stand-up tour from Jan. 26, 2016, in San Diego through April 24, 2016, in Oklahoma City. Titled “Making America Great Again!”, it is his first tour in six years.
On the January 10, 2016, broadcast of the National Public Radio-syndicated quiz show Ask Me Another, Cross appeared as a celebrity guest and performed well enough that at the audience's request the show's producers took the unusual step of allowing him to advance to the show's final, championship round; he then won that round and became that episode's overall champion, winning a prize package that included a pair of denim cutoff shorts that he himself had autographed.
Cross has said his comedic influences include Bill Hicks Andy Kaufman, Monty Python's Flying Circus, Lou Costello, Steven Wright, Richard Pryor, and Lenny Bruce.
In October 2005, Cross was sued by Nashville club owner Thomas Weber, who accused Cross of taping him without permission for Shut Up You Fucking Baby and Let America Laugh in violation of Weber's privacy rights. In April 2006, the case against Cross himself was dismissed and the case proceeded with Warner Music, Subpop Records, WEA Corporation, and the Alternative Distribution Alliance.
In a 2012 interview with Playboy magazine, Cross revealed that he had snorted a small amount of cocaine at the 2009 White House Correspondents' Dinner. Cross said, "It wasn’t like I got high...It was just about being able to say that I did it, that I did cocaine in the same room as the president."
In April 2005, Cross criticized stand-up comedian Larry the Cable Guy in a Rolling Stone interview, saying, "It's a lot of anti-gay, racist humor—which people like in America—all couched in 'I'm telling it like it is.' He's in the right place at the right time for that gee-shucks, proud-to-be-a-redneck, I'm-just-a-straight-shooter-multimillionaire-in-cutoff-flannel-selling-ring-tones act. That's where we are as a nation now. We're in a state of vague American values and anti-intellectual pride."
In response, Larry devoted a chapter in his book GIT-R-DONE to Cross and the "PC left", claiming that Cross had "screwed with my fans, it was time for me to say something". Larry claimed that Rolling Stone was baiting comedians to attack him, and they turned to Cross only after Lewis Black refused (due to the fact that Larry and Lewis are good friends). Cross responded with An Open Letter to Larry the Cable Guy posted on his website. He continued to mock Larry in his stand-up, satirizing Blue Collar TV during a guest appearance on Wonder Showzen. In December 2005, he ended his performance on Comedy Central's Last Laugh '05 by mockingly yelling Larry's catchphrase, "GIT-R-DONE!", to the audience as he left the stage. He pokes fun at Larry's comedy in Freak Show with a character called "Danny the Plumber Guy".
Cross has criticized Inside the Actors Studio host James Lipton on a Mr. Show sketch and in his stand-up performance The Pride Is Back, calling him "pretentious." Lipton, who thought that Cross's impression of him was not good-natured, would later appear alongside Cross in Arrested Development, in the recurring role of Prison Warden Stefan Gentiles. During filming, Cross was impressed with Lipton's acting and comedic ability, and the two became good friends. On one commentary track for season four of Mr. Show, Cross discussed the encounter, complimenting Lipton for his professionalism and performance, saying that he liked Lipton personally but still "didn't care for" Inside The Actors Studio.
Responding to critics of his decision to appear in the critically panned, but commercially successful, Alvin and the Chipmunks, Cross noted that the film paid for a summer home, and more than "all my other projects combined: book, TV show, the two pilots, Year One, yeah." Although he has admitted to taking the role primarily for the money, he has said that he does not regret doing so or consider it to be "selling out" as he has nothing against entertainment designed for children to enjoy that does not send a bad message. Cross reprised his Chipmunks role in the film's two sequels, Alvin and the Chipmunks: The Squeakquel and Alvin and the Chipmunks: Chipwrecked. In 2011, Cross said the third film was "the most unpleasant experience I've ever had in my professional life." He stated that this was due to clashes with one particular producer involved in the movie that he would not name, though he specified that it was not anyone in the cast, nor the director, and later posted a note to his Facebook page clarifying that it was not executive producers Janice Karman or Ross Bagdasarian, Jr. either, whom he stated "were never anything but warm, giving, and gracious" and regretted that some speculated they were the producers to whom he referred.
Cross has been critical of several pop music acts in his standup comedy, notably Creed and its lead singer, Scott Stapp. On his 2004 album It's Not Funny, Cross referred to Creed as "the third-worst band in history," and maligned the group's pop sensibilities for being too ubiquitous, suggesting that Stapp hung around "10th grade girls' locker rooms" to find inspiration for his song lyrics. Cross then relates an anecdote about Stapp being a last-minute replacement for another celebrity at a taping of Celebrity Poker Showdown in 2003. Cross became concerned that a confrontation would take place since he had "said the most awful shit about that guy [Stapp] on stage and in print." Cross said that as the taping was preparing to commence, he approached Stapp and extended his hand, introducing himself, and that Stapp shook his hand and sarcastically intoned, "Thanks for the words," to which Cross replied, "Well, you know..."
Cross was raised Jewish and later became an atheist. He describes his "political philosophy [as] definitely more socialist Democrat than centrist politician".
In August 2011, after four years of dating, Cross became engaged to Amber Tamblyn. They married in 2012. On February 21, 2017, Tamblyn announced that she and Cross had recently had a daughter, whose name she jokingly claimed via Instagram to be Dauphinoise Petunia Brittany Scheherazade Von Fünkinstein Mustard Witch RBG Cross Tamblyn-Bey jr. In March 2017, their child's name was officially announced as Marlow Alice Cross.
On September 26, 2013, Kickstarter co-founder Yancey Strickler revealed that Cross was the first investor in the crowdfunding platform. Strickler included Cross among the "friends and family" who first financed Kickstarter in 2006.