In 2000 Stamatopoulos and Robert Smigel pitched Comedy Central a spin-off of Smigel’s TV Funhouse cartoons (which were appearing singly as animated shorts on Saturday Night Live episodes) as a half-hour sketch comedy show. The standalone TV Funhouse show premiered in 2000 but was canceled after one season. He later joined the writing staff on Mad TV.

Stamatopoulos worked as a creative consultant and contributing writer on the first season of Tom Goes to the Mayor, with Tim & Eric and Bob Odenkirk. He also provided the voice of Drinky Crow on The Drinky Crow Show, which aired for one season on Adult Swim. His stop motion animated series Moral Orel premiered on Adult Swim on Christmas 2005 and aired for three seasons, airing its final episode in December 2008; a follow-up special aired in 2012. Following Moral Orel, Stamatopoulos created Mary Shelley’s Frankenhole, a stop motion series, for Adult Swim. It ran for two seasons from 2010 to 2012.

Stamatopoulos was a writer and producer on the 2010 NBC sitcom Community. He also played the recurring role of Alex “Star-Burns” Osbourne, a character whose nickname derived from his large star-shaped sideburns and his tendency to define himself by them. Together with Community creator Dan Harmon, Stamatopoulos started production company Starburns Industries.

Stamatopoulos and friend Andy Dick hosted a weekly podcast, Dino and Andy’s Skull Juice, which premiered in late 2016 and was initially produced by Feral Audio. Due to an on-air incident of hostility in mid-2018, Dick was asked to leave the podcast. Stamatopoulos asked friend and recurring guest Dana Snyder to replace Dick as co-host, and the podcast was renamed Dino & Dana’s Safe Space. Additional co-hosts Laetitia “Tish” Burns and Spencer Crittenden were also given billing in the podcast.