After beginning his career in 1995 on Def Comedy Jam, he was a writer and performer on NBC's Saturday Night Live (2003–2006).

He also portrayed a fictionalized version of himself on the BET improv-comedy reality television parody Real Husbands of Hollywood (2013–2016).

[2] Smoove was a regular cast member on the HBO comedy Curb Your Enthusiasm beginning in its sixth season in 2007, playing Leon Black.

[11] Although at that time he lived on the East Coast, he visited Los Angeles for the funeral of his friend, music producer Oji Pierce, enabling him to audition for Curb Your Enthusiasm.

[13] He had a major role for seasons two and three on the FOX network sitcom 'Til Death with Brad Garrett and Joely Fisher.

Smoove was also a cast member on the short-lived sketch comedy program Cedric the Entertainer Presents.

He also played a supporting role in Season 4, Episode 7, "The Vapora Sport" in the American sitcom The League on FX.

[5] He provides the voice of Dr. Ray De Angelo Harris, host of the Chakra Attack radio show in the video game Grand Theft Auto V. Smoove appeared in the 2013 film Dealin' with Idiots as Coach Ted.

He appeared as a guest judge on the first season of the FOX reality singing competition The Masked Singer.

[18][19] In 2020, Smoove starred in Mapleworth Murders opposite Paula Pell (another former writer for Saturday Night Live) and John Lutz for Quibi, which was produced by, among others, Lorne Michaels and Seth Meyers of SNL.

[20] Smoove won the 2021 Primetime Emmy Award for Outstanding Actor in a Short Form Comedy or Drama Series for his role.

[27] In 2019, Smoove played for the "Home" roster during the NBA All-Star Celebrity Game at the Bojangles' Coliseum in Charlotte, North Carolina.