Colin Quinn was born in Brooklyn to an Irish-American family and was raised in the Park Slope section of the borough. His exaggerated gravelly Brooklyn accent and idiosyncratic mannerisms are trademarks of his stand-up act, headlining at top comedy clubs across the country, including Caroline's Comedy Club in New York City.

Before becoming a comedian, Quinn worked as a bartender. He stopped drinking in the early 1980s after several bad experiences with alcohol, including drunken blackouts and nights spent in jail.

After quitting bartending, Quinn began his stand-up career in 1984. He first achieved fame in 1987 as co-host of the MTV game show Remote Control, which he did for three years.

In 1989, he hosted A&E stand-up showcase Caroline's Comedy Hour, and acted in and wrote the comedic short Going Back to Brooklyn along with Ben Stiller. Much of his early comedy career focused on stand-up and writing for shows like In Living Color. He later co-wrote the story and was an associate producer for the movie Celtic Pride, starring Damon Wayans and Dan Aykroyd.

In 1995, Quinn was hired by Saturday Night Live as a writer and featured player until 1997–1998 season, when he became a full cast member. He established himself on the show with characters such as "Lenny the Lion" and "Joe Blow", and did the recurring segment "Colin Quinn Explains the New York Times".

Quinn took over as host of the Weekend Update segment in January 1998 after Norm Macdonald's firing, and anchored the segment until departing SNL in 2000. Quinn would often comment on the highly publicized media circuses such as Clinton-Lewinsky Scandal and the Microsoft Anti-Trust Trial.

At the end of each Weekend Update segment, he would use the catchphrase, "That's my story and I'm sticking to it," a line from a 1993 hit country song from Collin Raye. During his time on SNL, Quinn often struggled to read from cue cards or a teleprompter. He was not thrilled about his run on the show, declaring on an episode of Tough Crowd, "I don't miss it."

During his SNL years, Quinn made his Broadway debut in his one-man show, Colin Quinn: An Irish Wake co-written with fellow comedian Lou DiMaggio, and was offered the role of Scott Evil in Austin Powers: International Man of Mystery by Mike Myers, which he turned down to make time for his writing projects. The role was taken by Seth Green.