Weathers was born in New Orleans, Louisiana. His father was a day laborer. As an eighth-grade student, he earned an athletic scholarship to St. Augustine High School, a private high school. During high school, he was an all-around athlete, involved in boxing, football, gymnastics, judo, soccer, and wrestling. He graduated in 1966.
Weathers played football as a defensive end in college. 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 for the San Diego State Aztecs in 1968 and 1969, playing for head coach Don Coryell.
After he went undrafted, Weathers signed with the Oakland Raiders as a free agent in 1970. Now playing as a linebacker, Weathers played seven games for the Raiders in 1970 and one in 1971. The Raiders released Weathers, and he signed with the BC Lions of the Canadian Football League in 1971 and played until 1973, 18 games in total. During the off-seasons, Weathers attended San Francisco State University and finished his B.A. in Drama in 1974. He retired from football in 1974, and began pursuing an acting career.
Weathers narrated NFL Films' season recap of the 1999, 2000 and 2001 seasons. During the 2017 NFL Draft, he appeared on NFL Network's pre-draft coverage.
Weathers began working as an extra while still playing football. He had his first significant roles in two blaxploitation films directed by his longtime friend Arthur Marks: Bucktown (1975) and Friday Foster (1975). Weathers also appeared in an episode of the 1970s sitcom Good Times entitled "The Nude", portraying an angry husband who suspected his wife of cheating on him with J.J. In 1975, he guest starred in an episode of Kung Fu entitled "The Brothers Caine". In 1976, he appeared as a loan shark in an episode of the crime-drama Starsky and Hutch.
When Weathers auditioned for the role of Apollo Creed longside Sylvester Stallone in Rocky, Weathers criticized Stallone's acting, that led to him getting the role. He reprised the role of Apollo Creed in the next three Rocky films in 1979, 1982, and 1985.
Weathers is briefly seen as an Army MP in one of the three released versions of Close Encounters of the Third Kind (originally released in 1977). In 1978, Weathers portrayed misogynist Vince Sullivan in a TV movie, Not This Time. In the late 1970s and 1980s, Weathers 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). 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 co-starred in the Adam Sandler comedy Happy Gilmore, as Chubbs, a golf legend teaching Happy how to play golf. He reprised the role nearly four years later in the Sandler comedy Little Nicky.
During the final two seasons of In the Heat of the Night, his character, Hampton Forbes, replaced Bill Gillespie as the chief of police. 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 three 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.
Weathers provided the voice for Colonel Samuel Garrett in the Pandemic Studios video game Mercenaries: Playground of Destruction. In 2005, he was a narrator on Conquest! The Price Of Victory - Witness The Journey of the Trojans!, an 18-part television show about USC athletics. Weathers is a principal of Red Tight Media, a film and video production company that specializes in tactical training films made for the United States armed forces. He also appeared in one episode of ER as the father of an injured boxer during their 2008 finale season.
For the penultimate film in the Rocky series, Rocky Balboa (2006), Stallone asked Weathers, Mr. T, and Dolph Lundgren for permission to use footage from their appearances in the earlier Rocky movies. Mr. T and Lundgren agreed, but Weathers wanted an actual part in the movie, even though his character had died in Rocky IV. Stallone refused, and Weathers decided not to allow Stallone to use his image for flashbacks from the previous Rocky movies. They instead used footage of a fighter who looks similar to Weathers.
Weathers portrayed the father of Michael Strahan and Daryl "Chill" Mitchell's characters on the short-lived 2009 Fox sitcom Brothers. Weathers is currently acting as Brian "Gebo" Fitzgerald in advertising for Old Spice's sponsorship of NASCAR driver Tony Stewart. He also appears in an ongoing series of web-only advertisements for Credit Union of Washington, dispensing flowers and the advice that "change is beautiful" to puzzled-looking bystanders. He is also starring in a series of commercials for Bud Light, in which he introduces plays from the "Bud Light Playbook". At the conclusion of each commercial, Weathers can be seen bursting through the Bud Light Playbook and shouting "Here we go!".
Weathers and his ex-wife, Mary Ann, have two children.