The son of a Baptist minister, Arsenio was a magician as a child. He attended Ohio University (in Athens, OH) before transferring to Kent State University. In 1988, he costarred in the comedy film Coming to America with Eddie Murphy.

Unknown to many, Arsenio was cast as the voice of Winston Zeddmore in the kids cartoon, The Real Ghostbusters from 1986-1987.

In 1989, he began hosting The Arsenio Hall Show, which lasted until 1994. His show was known for the audience's shouting "Woof Woof Woof". He also had a rivalry with Jay Leno after he was named host of The Tonight Show, during which Arsenio said that he would "kick Jay's ass" in the ratings game. The two have since patched up their differences and Arsenio has made numerous appearances on The Tonight Show.

Also in 1989, Arsenio released an album on MCA, Large and In Charge, under the moniker of "Chunky A". Chunky A was supposed to be Arsenio's overweight "little brother". For a while, the public did not realize that Chunky a was in fact Arsenio. The album had one minor hit "Owww!" and featured guest rappers Ice-T and KRS-1.

The title of the C&C Music Factory dance single "Things That Make You Go Hmmmm..." was inspired by Hall's monologue routines. He was also the target of most jokes as Keenen Ivory Wayans potrayed him on his sketch comedy show In Living Color.

After The Arsenio Hall Show ended, Hall made only infrequent appearances on television (including a short-lived 1997 sitcom called Arsenio) before starring in Martial Law with Sammo Hung from 1999-2000 and hosting the revival of Star Search in 2003.

Arsenio made a cameo appearance as himself in Chappelle's Show in March 2004, when Dave is imagining "what Arsenio is doing right now" in a dinner scene. It shows Arsenio at a wine party eating some cheese and saying, "Damn! That's some good-ass cheese!" After which, Arsenio starts punching and slapping people for not telling him about the apparently delicious cheese.