VelJohnson was born Reginald Vel Johnson on August 16, 1952 in Queens, New York, the son of Eve, a nurse, and Reginald Johnson, Sr., a hospital attendant. His father left the family, which included Reginald's brother Barry, when VelJohnson was 13 years old. Their mother subsequently married John Reilly. VelJohnson attended Benjamin N. Cardozo High School where he was classmates with George Tenet, and porn star Ron Jeremy. He later obtained a Bachelor of Arts from New York University. Before embarking on an acting career, he changed his name from Reginald Vel Johnson (his birth name) to Reginald VelJohnson. He later said he changed the spelling, "because I wanted a name people would remember."

VelJohnson is known for playing police officers in films and on television. In Ghostbusters, he had a brief appearance as a Municipal Corrections Officer, and in Crocodile Dundee, he plays a limo driver. VelJohnson played Sgt. Al Powell in the 1988 film Die Hard and later reprised the character in the 1990 sequel Die Hard 2, for which he still received fourth billing. He also portrayed a yelling apartment resident for promoting Instant Lottery games for a Michigan Lottery commercial in 1988. VelJohnson also played a police officer alongside Tom Hanks in Turner & Hooch (1989). Johnson was cast as police officer Carl Winslow in the sitcom Family Matters alongside Jo Marie Payton, who played his wife Harriette Winslow; he starred on that show until 1998. He also had a minor role in the 2002 film Like Mike. VelJohnson reprised his role of Sgt. Al Powell in the GameCube video game title, Die Hard: Vendetta, also in 2002. In 2004, he took the title role in the off-Broadway show She all Dat! (playing "she"). Since the end of Family Matters, besides making a few guest appearances on TV shows, VelJohnson has done mostly theater work. He wrote a critically acclaimed series of short stories called Division Street. One of them, called Sunday Evening Haircut, was made into a short film in 2005, which starred VelJohnson himself, alongside Kiki Shepard. VelJohnson has also made guest appearances in several TV shows, including The Equalizer, Diagnosis: Murder, Twice in a Lifetime, Will & Grace, Monk, CSI: Crime Scene Investigation, Eve, Crossing Jordan, The Parkers, That's So Raven, Chuck, in which he reprises his role as Al Powell, and Bones.

In 2007, he appeared in the short films Reverse, Nerve Endings, and Time Upon A Once which were made during the reality show On the Lot. The following year he appeared as the "Sgt. Al Powell" character from the Die Hard series in an episode of NBC's Chuck entitled "Chuck Versus the Santa Claus", as the cousin of Big Mike (Mark Christopher Lawrence). In 2010, VelJohnson started a recurring role as the principal on the Disney sitcom I'm in the Band and also Funny or Die.com's short HBO film entitled Just 3 Boyz starring Tim Heidecker, Eric Wareheim, and Zack Galifianakis. He has also appeared in the comedy film, The Formula, starring alongside Brandon Baker and Sasha Jackson.