D'Elia has been performing stand-up comedy since 2006. He considers himself to be a stand-up comedian who acts. He has been featured on Comedy Central's Live at Gotham, Comedy Central Presents, and Showtime's Live Nude Comedy.

He was introduced to a broader audience as a regular on the series Glory Daze, which ran for one season on TBS. He was initially cast only for the pilot and was later made a series regular. He then co-starred in the NBC comedy series Whitney, opposite comedian Whitney Cummings, for two seasons.

D'Elia was one of three hosts of the Ten Minute Podcast (2012–2015), along with Bryan Callen and Will Sasso. Since February 2017, he has hosted the weekly podcast Congratulations with Chris D'Elia, which has charted in the top 20 comedy podcasts in multiple countries. In January 2013, D'Elia released his debut parody rap album, as MC "Chank Smith", called Such Is Life.

On December 6, 2013, D'Elia's first one-hour stand-up special, White Male Black Comic, aired on Comedy Central. He has had three subsequent comedy specials: Incorrigible (2015), Man On Fire (2017) and No Pain (2020), all of which aired on Netflix. These were directed by his father, with the exception of No Pain which was directed by his brother.

D'Elia had a lead role in the 2014–2016 NBC sitcom Undateable as Danny Burton, a ladies' man whose friends are all in one way or another "undateable". In 2016, D'Elia headlined the Leafly 420 Comedy Tour show in Chicago with special guest Ron Funches.

In March 2019, it was announced that D'Elia had been cast in the recurring role of Henderson on the second season of the Netflix thriller series You.