Leary was born in Worcester, Massachusetts, the son of Irish Catholic immigrants Nora, a maid, and John Leary, an auto mechanic. Leary holds both Irish and American citizenship. He graduated from Saint Peter-Marian High School in Worcester. Through marriage, Leary is a distant cousin of talk show host Conan O'Brien, and has jokingly said on Late Night with Conan O'Brien that "All Irish people are related." His name is often misspelled as "Dennis", instead of "Denis."

Leary started his career as a comedian in the notorious Boston comedy scene of the 1980s, where he hosted his own show at the underground club "Play It Again Sam". He also wrote and appeared on a local comedy series, Lenny Clarke's Late Show, hosted by his friend Lenny Clarke and written by Boston comedy writer Martin Olson. Leary and Clarke both spoke about their early affiliations and influences in the Boston comedy scene in the documentary film When Standup Stood Out (2006). It was during this time that he developed his stage persona. He also appeared in skits on the MTV game show Remote Control, playing such characters as Keith Richards of the Rolling Stones, the "brother" of cohost Colin Quinn and artist Andy Warhol.

Although he says he is most at home on stage doing stand-up, Leary has appeared as an actor in over 40 movies, including The Sandlot, Monument Ave., The Matchmaker, The Ref, Suicide Kings, Dawg, Wag the Dog, Demolition Man, The Thomas Crown Affair and Operation Dumbo Drop. He has had the lead role in two television series, The Job and Rescue Me. In addition, Leary has provided voices for characters in animated films such as a medium fire-breathing dragon, Flame from the The Agents series, a saber-toothed tiger named 'Diego' in Ice Age and its sequel Ice Age 2 and 'Francis' in A Bug's Life. He has produced (and still produces) numerous movies, television shows, and specials through his production company Apostle; these include Comedy Central's Shorties Watchin' Shorties, the stand-up special Denis Leary's Merry F#$%in' Christmas, and the movie Blow. As a Boston Red Sox fan, he narrated the official 2004 World Series film. In 2006, Leary and Lenny Clarke appeared on television during a Red Sox telecast and, upon realizing that Red Sox 1st baseman Kevin Youkilis is Jewish, delivered a criticism of Mel Gibson's anti-semitic comments. As a hockey fan, Leary also hosted the National Hockey League video, NHL's Greatest Goals.

In 2003, Comedy Central honored Denis Leary in the Comedy Central Roast of Denis Leary. Friend Jeff Garlinacted as roastmaster. Roasters included Mario Cantone, Adam Ferrara, Jim Breuer, Nick DiPaolo, Don Gavin, Christopher Walken, Lenny Clarke, Gina Gershon Conan O'Brien, Gilbert Gottfried, Colin Quinn and Michael J. Fox

Leary is now the star and co-creator of FX's Rescue Me. He plays Tommy Gavin, a New York City fire fighter dealing with alcoholism, family dysfunction, and other issues in post-9/11 New York City. Leary received Emmy nominations in 2006 and 2007 for Outstanding Lead Actor in a Drama Series for his performance. For this tv-series, he turned down roles in two films: The Departed (Mark Wahlberg got the role after Leary turned down the role) and Bobby, which his close friend Emilio Estevez directed.

Leary recently did the TV voiceover for MLB 2K8 ads, where he used his trademark rant style in baseball terms. He was also a producer of the FOX show Canterbury's Law and wrote and directed its pilot episode. Canterbury's Law aired in the spring of 2008 but was canceled after eight episodes. He is currently working in the Ice Age: Dawn of the Dinosaurs movie, which will be released July 1, 2009.

Denis Leary has been married to writer Ann Lembeck Leary since 1989. They met when he was her instructor for an English class at Emerson College. They have two children, son John Joseph "Jack" (born 1990) and daughter Devin (born 1992). Ann Leary published a memoir, An Innocent, a Broad, about the premature birth of their son on an overseas visit to England.