Hall was born in Cleveland, Ohio, the son of Fred and Annie Hall. His father is a Baptist minister. Hall performed as a magician when he was a child. He graduated from Warrensville Heights High School in Warrensville Heights, Ohio, in 1973, after he briefly attended John F. Kennedy High School. He later attended college at Kent State University.

Hall later moved to Chicago, and then Los Angeles, to pursue a career in comedy, making a couple of appearances on Soul Train. In 1984, he was the announcer/sidekick for Alan Thicke during the short-lived talk show Thicke of the Night (a role for which he has on occasion noted his confusion with Monty Hall).

In 1986, the Fox network introduced The Late Show Starring Joan Rivers, created to directly challenge The Tonight Show Starring Johnny Carson. After a moderate start, ratings for the show sagged. Behind-the-scenes relations between Rivers and network executives at Fox quickly eroded, and Rivers left in 1987. The series was subsequently renamed The Late Show, and featured several interim hosts, including Ross Shafer, Suzanne Somers, Shawn Thompson, Richard Belzer and Robert Townsend before it was canceled in 1988. Hall was also chosen to host the show in the fall of 1987, and his stint proved to be immensely popular, developing a cult following which eventually led to Hall landing his own show in syndication.

He was also the original voice of Winston Zeddemore in the cartoon The Real Ghostbusters from 1986 to 1987. In 1988, he co-starred in the comedy film Coming to America with Eddie Murphy.

Between 1988 and 1991, Hall hosted the MTV Video Music Awards. Over the years, he has appeared as a guest on numerous talk shows, in special features, as a voice actor, on game shows and other award shows. Since The Arsenio Hall Show ended, Hall had a leading role on television shows such as the short-lived sitcom Arsenio (1997) and Martial Law with Sammo Hung (1998–2000), as well as hosted the revival of Star Search (2003–2004). While hosting Star Search, he popularized the catchphrase “Hit me with the digits!”.

In 1997, after being out of the public eye for three years, Hall gave an interview to dispel rumors regarding what had driven him off stage stating, “I went on the Internet and read I was in detox at Betty Ford, I got online under a fake name and typed in, ‘I know Arsenio better than anyone else and he’s not in detox, you idiots!'”

Hall has one son, born in 1998. Since the child’s birth, Hall mostly took time off to raise his son before resuming The Arsenio Hall Show in 2013. Hall had an interest in returning to the business eventually, but his decision was not confirmed until he appeared on Lopez Tonight in 2009 (although he initially considered a weekend show because he didn’t want to compete in ratings against his friend George Lopez).

Hall appeared as himself in Chappelle’s Show in March 2004, (convinced by the Swedish comedy director Saman Khadiri), when Chappelle was imagining “what Arsenio is doing right now” in a dinner scene. Hall has guest co-hosted Wednesday evenings on The Tim Conway Jr. Show on KLSX 97.1 FM radio. Hall also hosted MyNetworkTV’s comedic web video show The World’s Funniest Moments and TV One’s 100 Greatest Black Power Moves. Hall also appeared on Real Time with Bill Maher in May 2012, in a discussion commemorating the 1992 Los Angeles riots.

Hall was considered to be the host of the syndicated version of Deal or No Deal and filmed a pilot (there were six taped). However, by the time the syndicated series began on September 8, 2008, Howie Mandel was chosen as the host.

He also appeared regularly on The Jay Leno Show, and was a guest on Lopez Tonight. George Lopez credits Arsenio for being the reason he had a late night show; Lopez appeared on The Arsenio Hall Show more times than any other comedian. Lopez requested Hall be a co-host on Lopez Tonight (November 25, 2009) since he regarded Hall as his inspiration and the first “late night party show host”. Hall has filled-in as guest host for NBC’s Access Hollywood Live (2011) and CNN’s evening talk/interview program Piers Morgan Tonight in 2012.

In 2012, Hall was a contestant on the fifth edition of The Celebrity Apprentice, which began airing February 19, 2012. Hall represented his charity, the Magic Johnson Foundation, which is dedicated to advancing economic and social equality by engaging minorities in every aspect of their communities; increasing academic and innovative achievement; and raising HIV/AIDS awareness, treatment and prevention. While Hall clashed with Aubrey O’Day, he befriended a majority of the cast. On May 20, 2012, in the live season finale, Hall was chosen as the Celebrity Apprentice winner, being “hired” by billionaire real estate investor and future President of the United States Donald Trump over the other celebrity finalist, singer Clay Aiken. For winning The Celebrity Apprentice, Hall won the $250,000 grand prize for his charity, in addition to any money he won for his charity for tasks he and his team won when he was a team leader on the show.

On May 5, 2016, Hall filed a $5 million defamation lawsuit against Sinéad O’Connor after she claimed he had fueled Prince’s drug habit and also had spiked her drink during a party at Eddie Murphy’s house. Hall dropped the lawsuit after O’Connor apologized and retracted her allegation that he had supplied Prince with drugs.