Walsh was born in Chicago, the fourth of seven children of Dick and Audrey Walsh. He graduated from Hinsdale South High School in 1982. While in high school he played on the football team as a backup tight end. He attended Northern Illinois University, where he graduated with a degree in Psychology, also spending a year studying abroad in Austria at Salzburg College.
After college, his interest shifted to performing when he started taking improvisational comedy classes in Chicago, where he would become a regular performer at the Annoyance Theater and ImprovOlympic, where he studied under legendary improv teacher Del Close. In 1991, he met comedian Matt Besser, with whom he began performing stand-up comedy. Along with Matt Besser, Amy Poehler, and Ian Roberts, he is a founding member of the Upright Citizens Brigade improv comedy troupe and played "Trotter" in the troupe's sketch comedy series, which ran for three seasons on Comedy Central. Before the show, the UCB comedy foursome had already been doing improv shows at their theatre in New York, which used to be a burlesque house before they remodeled it to become a theatre. To date, they have founded four successful Upright Citizens Brigade comedy theaters located in New York at UCB Chelsea and The East Village UCB, and Los Angeles with UCB Franklin and UCB Sunset.
Besides his sketch work with the Upright Citizens Brigade, Walsh is also known for his memorable supporting roles in popular comedy films in recent years including Cyrus, Old School, The Hangover, Role Models, and Semi-Pro. Walsh also wrote and starred in the cult indie-comedy Martin & Orloff, which had a limited theatrical run in 2002 and 2003. In addition, he was also a correspondent on The Daily Show from 2001 to 2002, made regular appearances in comedy sketches on Late Night with Conan O'Brien and MTV's Human Giant as well as starring in the Comedy Central mockumentary series Dog Bites Man in the summer of 2006. Walsh has the distinction of having appeared in several Todd Phillips comedy films, most often playing characters aptly named "Walsh".
In 2010, Walsh created the improvised comedy series Players for Spike TV. Walsh (creator, writer, director and executive producer of the show) stars in the series alongside his Upright Citizens Brigade partner Ian Roberts, as two brothers who run a sports bar together. The show aired for one season, concluding on August 14, 2010.
Walsh currently hosts the podcast Bear Down with comedian Scot Armstrong (screenwriter of Old School) where they discuss their favorite football team The Chicago Bears and do sports-themed comedy bits such as fake call-ins and in-character interviews. The podcast has also featured appearances by comedians such as Horatio Sanz, Ian Roberts, Joseph Nunez, and Matt Price.
In 2010, Walsh had recurring roles on the NBC comedy series Outsourced and on the HBO comedy series Hung. In 2012, he began co-starring as Mike McLintock in the HBO series Veep, for which he was nominated for the Primetime Emmy Award for Outstanding Supporting Actor in a Comedy Series in 2016. During that year, Walsh portrayed J. R. R. Tolkien in The Dead Authors Podcast.
Walsh's directed his first feature film High Road, an indie-comedy he co-wrote with Josh Weiner. The film was released on March 6, 2012. He is currently in post-production for his second directed film, A Better You, which he co-wrote with Brian Huskey, who stars in the film.
In the movie Into the Storm, Walsh stars as Pete Moore, who is the driver of the Tornado Intercept Vehicle nicknamed "Titus."
He will be appearing in the MyCareer mode in the upcoming basketball simulation game, NBA 2K17.
Walsh lives in Toluca Lake, California, with his wife Morgan. They have three children, Jude, Emmett, and Celia, and three dogs named Roger, Sarah, and Penny.
Walsh confirmed on the May 20th, 2016 episode of the Dan Patrick Show that along with the Bears he is also a fan of the Chicago White Sox.