Miller was born in Denver, Colorado, the son of Leslie Miller, a clinical psychologist, and Kent Miller, an attorney.
He attended Graland Country Day School and graduated from Denver's East High School, where he participated in drama productions. His drama teacher at East High, Melody Duggan, confirms Miller was a "typical class clown", but said he was much more intuitive than the average teenager. "He understands the frailty of the human condition better than any kid I've ever had.
In 2003, Miller graduated from George Washington University in Washington, D.C. with a B.A. in psychology with a concentration in situation theory and social influence.
At GWU, he was a member of the comedy group receSs and the Lambda chapter of Phi Sigma Kappa fraternity. While in college, Miller studied the circus arts at Frichess Theatre Urbain in Paris, and attended the British American Drama Academy in London, where he studied Shakespeare for a summer.
After college, Miller moved to Chicago and began to perform improvisation and stand-up comedy, performing with many local troupes. He toured with The Second City for two years. In 2008, he was named one of Variety's 10 Comics To Watch.
In 2011, Miller released an hour comedy special, No Real Reason in 2011, and a comedy album, Mash Up Audiofile in 2012.
In 2015, he was part of Funny or Die’s Oddball Comedy and Curiosity Festival, a touring show which included Amy Schumer, Aziz Ansari, and other comics.
On June 17, 2017, HBO premiered his hourlong comedy special, T.J. Miller: Meticulously Ridiculous, which was filmed in Miller's native Denver at the end of his 2016 Meticulously Ridiculous Tour.
Miller appeared frequently as a member of the "round table" on Chelsea Lately. He appeared as Marmaduke Brooker in Carpoolers, which ran for 13 episodes on ABC in 2007–2008. In 2012, he voiced Robbie Valentino on the Disney channel cartoon Gravity Falls. On December 13, 2010, October 28, 2011, and June 14, 2012, he performed stand-up on Conan. On November 15, 2011, his stand-up special No Real Reason premiered on Comedy Central. In 2011, he hosted a special called Mash Up, which was picked up in 2012 for a full season by Comedy Central. He starred in the Fox TV series The Goodwin Games as Jimmy Goodwin.
Miller starred in the HBO sitcom Silicon Valley, which has been met with widespread critical acclaim and he won the Critics' Choice Television Award for Best Supporting Actor in a Comedy Series in 2015. In May 2017, Miller and HBO jointly announced that Miller will not be returning for the 5th season of Silicon Valley.
As a commercial actor, He voices a talking ball of mucus in commercials for Mucinex and stars as Greg the Genie in a promotional campaign for Slim Jim meat snacks.
In Miller's film debut, Cloverfield, he appeared onscreen for only a few minutes, but his voice was heard in almost every scene as the character who videotaped most of the events depicted. In 2009, he played Cessna Jim in The Goods: Live Hard, Sell Hard and the dim-witted grindcore musician Rory in Mike Judge's comedy Extract. In 2010, he co-starred in She's Out of My League as Stainer, played Brian the Concierge in Get Him to the Greek and appeared in a supporting role in the film Unstoppable.
He voiced the character ‘Tuffnut’ in the Oscar-nominated animated films How to Train Your Dragon and How to Train Your Dragon 2. He also played Dan in Gulliver's Travels, released in December 2010. He played the supporting character of Ranger Jones in the live-action/animated Yogi Bear 2010 film.
Unlike his character on the cartoon show, he is "dumb-but-not-in-a-funny-way", according to the Buffalo News. He was cast in the part after two auditions; as a joke, he sent Warner Bros. an improvised video audition with an actual bear, though he had already been offered the part before they received it.
In 2011, he appeared in the film Our Idiot Brother. He had a cameo as administrative personnel for Rolling Stone in the 2012 film Rock of Ages. He starred in the 2016 movie Search Party alongside Adam Pally.
In 2014, he appeared in Transformers: Age of Extinction.
In November 2014, he was the voice of Fred in the superhero CGI film Big Hero 6. Miller portrayed Weasel in Deadpool. In 2017, he portrayed the voice of the main protagonist Gene, a meh emoji with different expressions, in the animated The Emoji Movie.
On September 12, 2011, Miller released a comedy rap concept album titled The Extended Play E.P. The album features comedians Bo Burnham, Doug Benson, Pete Holmes and hip-hop artists Ugly Duckling and Johnny Polygon.
In 2012, Miller released The Extended Play E.P. Illegal Art Remix Tape. Also in 2012, Miller released Mash Up Audiofile on Comedy Central Records to mixed reviews.
Miller started appearing on Chicago-based comedy Podcast Red Bar Radio in 2006 as a semi-regular co-host. He hosts a podcast with friend and fellow comedian Cash Levy, titled Cashing in With TJ Miller, which began airing in March 2012 on the Nerdist Network. He is also a frequent guest on Doug Benson's podcast Doug Loves Movies.
In 2014, Miller became engaged to his long-term girlfriend, actress and mixed-media artist Kathryn Gorney. They were married on September 6, 2015 at the Denver Botanic Gardens.
A self-described "enthusiastic marijuana user", Miller notes other similarities between himself and Erlich Bachman, his character on Silicon Valley. "He is just sort of, unfortunately for me, a magnification of certain aspects of my personality, mixed in with a couple of fictional things...I am, at times, a Falstaffian figure; he very much is that too. We are in line with each other as nihilists: He thinks you should tell it like it is ... because everybody's opinion including yours doesn't mean anything."
Miller described learning about an undiagnosed cerebral arteriovenous malformation on his right frontal lobe on the Pete Holmes podcast You Made It Weird on October 28, 2011. He stated that he became more philosophical, narrated his behaviors, and was unable to sleep while filming Yogi Bear in New Zealand in 2010. His brain surgery was successful, though there was a 10 percent risk of fatality.
On December 9, 2016, Miller was arrested and jailed in Los Angeles for allegedly assaulting a driver of the Uber car service company because of an argument he had with the driver over Donald Trump. He was released on his own recognizance after bail was set at $20,000.
Miller is an atheist.