Cole was on the writing staff for The Tonight Show with Conan O'Brien from 2009 to 2010, and worked as a writer for Conan from 2010 to 2012. He has appeared frequently in comedic bits for both broadcasts, and he has, along with the rest of the staff, received two Primetime Emmy nominations. Cole also performed on Conan O'Brien's "Legally Prohibited from Being Funny on Television Tour" in 2010.
Cole was on the cast of Angie Tribeca from 2016 to 2018 and has a recurring role on the ABC sitcom Black-ish as Charlie Telphy. Cole was promoted to a main role beginning with season 4. He then made some appearances in the Black-ish's spin-off Grown-ish.
Cole has performed stand up on other programs such as John Oliver's New York Stand-Up Show, Mash Up and Lopez Tonight. Cole created his own production company, Coled Blooded, to produce the sketch comedy show Deon Cole's Black Box. It premiered on June 10, 2013, on TBS, but it was canceled on October 25, 2013. Cole has hosted the game show Face Value on BET since 2017.
In 2017, he performed in a half-hour set in the Netflix original series The Standups.
In October 2019, Netflix released a stand-up special called Deon Cole: Cole Hearted.