Holmes has appeared on Comedy Central’s Premium Blend, as a regular panelist on VH1’s Best Week Ever, and on VH1’s All Access. His cartoons have appeared in The New Yorker. In 2010, he performed on John Oliver’s New York Stand Up Show as well as Late Night with Jimmy Fallon. On February 26, 2010, he performed his first television special on the series Comedy Central Presents. On March 21, 2011 and on November 17, 2011, he appeared on the TBS talk show Conan.

Holmes released his first album, Impregnated With Wonder, on iTunes in 2011. In 2013, he released his second album, Nice Try, The Devil. He released his third album, Faces and Sounds, in 2016. In 2019, he released his fourth album, “Dirty Clean.”  Holmes has created a comedic portrayal of Batman in CollegeHumor’s internet series Badman. He ran a YouTube channel which was focused around skits alongside Matthew McCarthy called frontpagefilms.

Holmes created and stars in the HBO series Crashing. The pilot was written by Holmes and directed by Judd Apatow. After the season three finale, it was announced that HBO had canceled the series. On May 14, 2019, Holmes released his book Comedy Sex God, which is described as, “Part autobiography, part philosophical inquiry, and part spiritual quest.”

On March 29, 2021, Holmes was selected to play the lead role of a laid-off auto worker-turned-professional bowler (based on the life of Tom Smallwood) in a CBS sitcom pilot. On May 14, 2021, the pilot for Smallwood was ordered to series, with a mid-season debut planned for 2021–22 television season.