Birbiglia was born in Worcester, Massachusetts, the son of Mary Jean (née McKenzie) and Vincent Paul Birbiglia. He is the youngest of four children. He is of part Italian descent and was raised Catholic. Birbiglia attended the all-boys Catholic school St. John’s High School for one year, and graduated from St. Mark’s School in 1996. He says seeing comedian Steven Wright perform inspired him to begin writing jokes at age 16. He subsequently attended Georgetown University in Washington, D.C., graduating in 2000. During college he performed as a member of the Georgetown Players Improv Troupe, worked as a server in a comedy club, and began performing at DC Improv (The Improv) in Washington, D.C.

Birbiglia began doing improv in 1997, his sister was able to get him an interview on Conan O’Brien’s show as an intern. Birbiglia moved to New York in 2000, and appeared on the Late Show with David Letterman in 2002. He told his first story on stage at the U.S. Comedy Arts Festival in Aspen, in 2003, and eventually became a semi-regular contributor to The Moth storytelling series. He released his first album, Dog Years, in 2004, followed by My Secret Public Album, Volume 1a (2005) a compilation of his appearances on The Bob and Tom Show. His next two albums, Two Drink Mike (2006), and My Secret Public Journal Live (2007) were released on Comedy Central Records. My Secret Public Journal Live was named one of the best comedy albums of the decade by The A.V. Club

In 2008 CBS picked up a sitcom pilot loosely based on Birbiglia’s life and featuring himself, Bob Odenkirk and Frances Conroy that ultimately never aired. He later called the failure of his pilot “the luckiest thing that ever happened to me.”

In 2008, Birbiglia opened Sleepwalk with Me, a one-man show that straddled standup comedy and theater, off-Broadway at the Bleecker Street Theater. The show was presented by Nathan Lane, and the New York Times called it “simply perfect”. Time Out New York named it their “Show of the Year” in 2009.

In 2011, Birbiglia mounted his second one-man show, My Girlfriend’s Boyfriend, which ran for four months off-Broadway and won the Lucille Lortel Award for Outstanding Solo Show. He toured My Girlfriend’s Boyfriend around the world with tour dates in the United States, Australia, Canada and the United Kingdom. On June 2, 2013, Birbiglia performed it for the last time at Carnegie Hall. My Girlfriend’s Boyfriend was featured as the number one stand-up special of 2013 by Vulture, Paste, The Laugh Button and Laughspin. It was also named one of Time Out New York’s Best Comedy Specials of 2013. Flavorwire listed the special as one of the top 20 funniest stand-up specials of all time.

Birbiglia’s Thank God for Jokes comedy special was released on Netflix on February 28, 2017.

In April 2017, Birbiglia announced a tour of his newest show titled The New One. The tour started with 25 cities and, in December 2017, featured a limited podcast titled The Old Ones. The podcast features Mike Birbiglia analyzing his old stand-up with guests including his brother Joe Birbiglia, comedians Pete Holmes and John Mulaney, film producer and director Judd Apatow, contributor to ‘This American Life’ Ira Glass and his wife. The New One made its off-Broadway debut at the Cherry Lane Theatre on July 26 and was scheduled to run through August 2 before a high demand for tickets extended the show’s run to and through August 26.