Born and raised in St. Louis, Missouri in a Roman Catholic family of Irish descent, Sean Gunn has four brothers and one sister. His brother James is a screenwriter/director, who took acting classes with Sean when they were children) and his brother Patrick is an executive producer for Artisan Entertainment.

Gunn attended the Jesuit St. Louis University High School (class of 1992) and graduated fromDePaul University’s Theatre School. After graduation, he started a theater company with friends. Gunn’s surname is from the Irish name MacGilGunn meaning “Sons to the Servants of the God of the Dead," therefore Gunn means “God of the Dead”.

In 1995 Gunn played Sammy Capulet in the B Film Tromeo and Juliet. In 2000, he guest starred in the second episode of Gilmore Girls as Mick, a freelance worker that does many things. As the first season continued, Gunn was brought back to play the recurring role of Kirk Gleason, one of Stars Hollow’s most eccentric citizens. Since 2002 until the end of the series in 2007, Gunn was a regular cast member of the show. He also has a recurring role on October Road as Rooster.

Although he is best known for his regular Gilmore Girls role, Sean Gunn also has several television show guest appearance credits, including Angel, 3rd Rock from the Sun, Yes, Dear, True Jackson, VP, Andy Richter Controls the Universe, and Bunheads. Gunn is currently seen in commercials as an “agent” for the text message information service KGB.com. In films, Gunn has also had several roles, the most substantial being Alien Orphan/Doug in The Specials, for which he also received a co-producer credit.

In 2003, Gunn starred in the featurette "The Man Who Invented the Moon," directed by fellow Goodman School of Drama alum and Gilmore Girls cast member John Cabrera. Gunn and Cabrera have been close artistic colleagues since their school days in Chicago back in the mid-nineties.

Along with his brothers James and Brian, he is a creator and actor in the spoof porn series, PG Porn. He also had a brief role as a computer maintenance man on the Nickelodeon show, True Jackson VP. Gunn starred in a series of television commercials for Knowledge Generation Bureau. He appeared in the 2010 film Super, written and directed by his brother James.  Sean is also the voice actor behind the character of Swan in the Warner Brothers video game Lollipop Chainsaw, written by his brother James. Gunn guest-starred in Glee (“Makeover”, Season 4) as committee member Phineas Hayes.

In 2013, Sean provided stand-in work for the characters of Rocket Raccoon and Thanos for the film Guardians of the Galaxy, which was written and directed by his brother. The characters were later voiced by Bradley Cooper and Josh Brolin. He also played the role of Kraglin.

In 2014, he held a supporting role in Bones on FOX in season 10 episode 5 “The Corpse at the Convention”