Armisen was born on December 4, 1966, in Hattiesburg, Mississippi. He moved with his family to New York as a baby and briefly lived in Brazil in his youth. He was raised in Valley Stream, New York, where he was a high school classmate of fellow SNL alumnus Jim Breuer. Armisen attended the School of Visual Arts in Manhattan before dropping out to begin a career as a rock drummer. He has mentioned watching the bands The Clash and Devo perform on television and wanting to be a performer since he was a child.

In 1984, Armisen played drums in a local band along with his high school friends in Valley Stream, New York, but the group soon ended. In 1988, he moved to Chicago to play drums for the punk rock band Trenchmouth, and in the 1990s he played background drums with Blue Man Group.

In 1998, he posed as a music journalist for the short film Fred Armisen’s Guide to Music and South by Southwest. It was filmed by then-girlfriend Sally Timms and featured Armisen’s “pranking musicians and industry types” during the South by Southwest festival in Austin, Texas. In various segments he asked self-described “stupid” questions, pretended to be German, and also acted blind. A year later, Armisen starred with alternative rock legend Steve Albini in Chevelle’s Point #1 EPK.

Armisen’s subsequent television work, such as some “memorable Andy Kaufman–esque appearances” on Late Night with Conan O’Brien, as well as work for Crank Yankers and Adult Swim, led to a role in 2002 as a featured player in the cast of Saturday Night Live. In the 2004 season, he was promoted to repertory cast member status.

Armisen joined the cast of Saturday Night Live in 2002. He was promoted to a repertory player in 2004. After 11 years as a cast member, he decided to leave the show. At the time of his 2013 departure from the show, Armisen was the third-longest tenured cast member (behind Seth Meyers and Darrell Hammond), and he appeared in the second-most number of sketches (856) of any cast member. Since then, Armisen has come back for multiple cameo appearances on the show, including when he hosted the season 41 finale on May 21, 2016, with musical guest Courtney Barnett.

Armisen has directed music videos for bands like The Helio Sequence. Armisen also had a role in the Wilco documentary I Am Trying to Break Your Heart, which featured footage from his stint opening for front man Jeff Tweedy’s 2001 solo tour. He also appeared in video segments on Blue Man Group’s How to be a Megastar Tour 2.0. Armisen occasionally writes for Pitchfork Media and interviewed Cat Power for that company. Fred appeared as Jens Hannemann on Jimmy Kimmel Live! on October 19, 2007, promoting a 28-minute DVD called Fred Armisen presents Jens Hannemann: “COMPLICATED DRUMMING TECHNIQUE”. In 2010, Armisen briefly joined Joanna Newsom’s tour for her album Have One on Me as his character Jens Hannemann. On SNL, Armisen often plays musical instruments in sketches, has two recurring characters who are musicians (Mackey the drummer from the Rialto Grande and Ferecito from Showbiz Grande Explosion), or impersonates famous figures in the music world such as Liberace, Phil Spector, Lou Reed, and Prince.

Further television work included an appearance on Parks and Recreation in the 2009 episode “Sister City”. For the Cartoon Network series The Looney Tunes Show (2011–2014), Armisen voices Speedy Gonzales. He and fellow Saturday Night Live alums Bill Hader and Seth Meyers write, produce, and star in the IFC mockumentary series Documentary Now! which premiered in 2015.

Armisen stars in the IFC sketch series Portlandia alongside Carrie Brownstein (of Sleater-Kinney); the first season debuted on January 21, 2011. With Brownstein, he appeared on the 2012 Simpsons episode “The Day the Earth Stood Cool”, in which they play the Simpsons’ new neighbors, who encourage everyone to be cool like them.

In 2013, Armisen appeared in the official music video for Portland, Oregon-based band Red Fang’s song “Blood Like Cream”.

In 2014, Armisen worked as bandleader on Late Night with Seth Meyers received positive reviews for his deadpan comedy, especially in his interplay with the host.

In late 2014, Armisen was featured on the popular comedy web series Comedians in Cars Getting Coffee with host Jerry Seinfeld.

In 2015, Armisen was the recipient of Smithsonian magazine’s American Ingenuity Award for Performing Arts.

Armisen is a fan of the video game Red Dead Redemption. On a 2018 episode of Larry King Now, he described himself as being “very good” at the game. This prompted the studio Rockstar Games to cast him in the next installment of the series, Red Dead Redemption 2. He is also a fan of black metal and death metal.