Fred “The Hammer” Williamson played college football for Chicago's Northwestern University during the late 1950s. This was followed by a seven-year professional career in the NFL, beginning in 1960 when he was signed on with the Pittsburgh Steelers. The following year, he joined the Oakland Raiders, with whom he played four seasons. He then played three seasons with the Kansas City Chiefs. It was during this time he became known as "The Hammer" and was a starter in the very first Super Bowl.

He moved into acting in the late 1960s, with one of his earliest TV roles being Anka in the Star Trek episode “The Cloud Miners.” He made his feature film debut playing Captain Oliver "Spearchucker" Jones in Robert Altman's irreverent 1970 comedy M*A*S*H.

From 1970 through 1971, Williamson made regular appearances on the television sitcom Julia, playing the title character's love interest, Steve Bruce.

For the remainder of the 1970s, Williamson was a fixture of action films in the "blaxploitation" genre. He also produced, directed and wrote a number of these films. He played the title role in films such as Black Caesar (1973) and Mean Johnny Barrows (1976, with Anthony Caruso), the latter of which he also directed and produced. Other notable films included Three The Hard Way (1974) and The Inglorious Bastards (1977).

Williamson did continue to appear on television during this time, including two episodes of Police Story, an episode of The Rookies, a CHiPs two-parter, and an episode of Ricardo Montalban's series Fantasy Island with Adrienne Barbeau. He also appeared in the 1978 mini-series Wheels.

Throughout the 1980s, Williamson worked on a number of Italian B-movies, mostly science fiction action films, including The New Barbarians and Bronx Warriors (both 1982) and The New Gladiators (1984). He also continued directing, producing, and starring in the occasional blaxploitation film, such as 1983's The Big Score.

Williamson became a regular on the short-lived TV series Half Nelson, which ran for seven episodes in 1985. In addition, he co-starred with Star Trek: The Motion Picture actress Persis Khambatta in the Italian science fiction film Warrior of the Lost World (1983) and in the 1988 direct-to-video thriller Deadly Intent.

Williamson continued to produce, direct, and star in action films throughout the 1990s and 2000s. He had a supporting role in Robert Rodriguez' hit 1996 vampire blood-fest From Dusk Till Dawn. More recently, he played Captain Doby in the 2004 feature film version of Starsky & Hutch. Other film credits include the 1996 crime thriller Original Gangstas, 1999's Whatever It Takes, 2000's Submerged, and 2007's Fighting Words.

In 2015, Williamson has been seen in numerous episodes of IFC’s popular series Comedy Bang Bang!