Small started learning guitar at 15, and graduated from the Berklee College of Music in 1997. During his music studies he concurrently took several writing and comedy classes at Emerson College. After graduating, he began performing stand-up at The Comedy Studio in Harvard Square, where he was spotted by Loren Bouchard, who at the time was casting for the central character for a UPN pilot produced by Tom Snyder Productions which eventually evolved into Home Movies.
Small was the co-creator, writer, voice actor, composer and musician for Home Movies, a cartoon initially aired on the UPN television network and then moved to Cartoon Network's Adult Swim. The final episode of Home Movies aired on April 4, 2004, after running four seasons, although the show is periodically rerun on Adult Swim. In the series, he voiced the show's protagonist, 8-year-old aspiring filmmaker Brendon Small, as well as a number of other characters.
Small's latest claim to fame is as co-producer, co-writer, composer, and actor for the Adult Swim series Metalocalypse, which premiered on August 6, 2006. The series focuses on a fictional death metal band named Dethklok, and each episode features a song "performed" by the band. In addition to all of the behind-the-scenes work he does for the series, he also provides voice talent for the characters Skwisgaar Skwigelf, Pickles the Drummer, and Nathan Explosion, three of the five members of Dethklok. The song "Thunderhorse" was also featured on the hit video game Guitar Hero II.