Weathers was born in New Orleans, Louisiana. He graduated from St. Augustine High School in 1966 and then went to Long Beach City College and San Diego State University. Outside of acting, he is a member of both Big Brothers and the United States Olympic Committee. In April 2007, he married Jennifer Peterson, a documentary filmmaker. He filed for divorce in Sept. 2008, and has since divorced -his third.

Weathers played football both collegiately and professionally as a linebacker. He started his college career in 1966 at Long Beach City College, where he did not play in 1966, due to an ankle injury suffered when he tripped over a curb surrounding the running track, while warming up for practice with another linebacker, Paul Snow. He then transferred and played for San Diego State University, becoming a Letterman in 1968 and 1969. This led to a brief professional career with the Oakland Raiders, where he played 7 games in 1970 and one game in 1971. He joined the BC Lions of the Canadian Football League in 1971 and played until 1973, 18 games in total. He retired in 1974 and became an actor.

In his football career, he played for hall-of-fame coaches Don Coryell (at San Diego State) and John Madden with the Oakland Raiders.

Weathers had his first parts in two blaxploitation films directed by his longtime friend Arthur Marks: Bucktown and Friday Foster (both 1975). Weathers also appeared in an episode on the 70's sitcom Good Times as an angry husband who suspected his wife of cheating on him with J.J.

In 1976, he starred alongside Sylvester Stallone in Rocky as Apollo Creed, a role he would reprise in the next three Rocky films in 1979, 1982 and 1985. For the final film in the Rocky series, Rocky Balboa, Sylvester Stallone asked Weathers, Mr. T, and Dolph Lundgren for permission to use footage from their appearances in the earlier Rocky movies. Mr. T and Dolph Lundgren acquiesced, but Weathers wanted an actual part in the movie, even though his character died in Rocky IV. Stallone refused and Weathers decided not to allow Stallone to use his image for Rocky flashbacks from the previous movies. They instead used footage of a fighter who looks similar to Weathers.

In 1978, Carl portrayed misogynist Vince Sullivan in a TV movie, Not This Time. Weathers also starred in a number of action films for the small and big screen, including: Force 10 from Navarone (1978), Predator (1987), Action Jackson (1988), and Hurricane Smith (1992). He is briefly seen as an Army MP in one of the three released versions of Close Encounters of the Third Kind. As a member of the cast of Predator, Weathers worked with future California governor Arnold Schwarzenegger and future Minnesota governor Jesse Ventura. Many years later he appeared in a spoof segment on Saturday Night Live, announcing that he was running for political office and urging viewers to vote for him on the basis that "he was the black guy in Predator".

He also appeared in Michael Jackson's "Liberian Girl" music video, and played Chubbs in Happy Gilmore, teaching Happy how to play golf.

During the final season of In the Heat of the Night, his character of Hampton Forbes replaced Bill Gillespie as the chief of police. He continued that role in the television movies based on the series. Another noted TV role was Sgt. Adam Beaudreaux on the cop show Street Justice. He also played as MACV-SOG Colonel Brewster in the CBS series Tour of Duty.

In 2004, Weathers received a career revival as a comedic actor beginning with appearances in 3 episodes of the comedy series Arrested Development as a cheapskate caricature of himself, who serves as Tobias Fünke's acting coach. He was then cast in the comedies The Sasquatch Gang and The Comebacks.

Weathers had a guest role in two episodes of The Shield as the former training officer of main character Vic Mackey.