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Armisen was the bandleader and frequent drummer for the Late Night with Seth Meyers house band, the 8G Band from 2014 to 2024. He was a cast member on the late-night sketch comedy and variety series Saturday Night Live from 2002 to 2013. He voiced Speedy Gonzales on The Looney Tunes Show. He also works as a voice actor in films, such as The Smurfs (2011), The Smurfs 2 (2013), The House of Tomorrow, The Lego Ninjago Movie (both 2017), The Mitchells vs. the Machines (2021), The Super Mario Bros. Movie, The Contestant (both 2023), Thelma the Unicorn (2024) and Fixed (2025).

Armisen has acted in comedy films, including EuroTrip, Melvin Goes to Dinner, The Ex, and The Dictator. He is also notable for his guest-star appearances in television shows such as 30 Rock, Parks and Recreation, Brooklyn Nine-Nine, New Girl, Broad City, Unbreakable Kimmy Schmidt, Difficult People, The Last Man on Earth, Toast of Tinseltown, Our Flag Means Death, Curb Your Enthusiasm, Modern Family, and Barry.

Armisen received a Grammy Award nomination for Best Comedy Album for Standup for Drummers in 2019. He has also won two Peabody Awards, one in 2008 as part of the Saturday Night Live political satire cast and one in 2011 for Portlandia. From 2019 to 2022, he co-starred and served as writer and executive producer on the Spanish-language series Los Espookys, which he co-created.