Kotto’s first marriage was to a German immigrant, Rita Ingrid Dittman, whom he married in 1959. They had three children together before divorcing in 1976. A week after his divorce, Kotto married Toni Pettyjohn, and they also had three children together, before divorcing in 1989. Kotto married his third wife, Tessie Sinahon, on July 12, 1998. Kotto is also Jewish.

His film debut was in 1963, aged 23, in an uncredited role in 4 For Texas. He performed in Michael Roemer’s Nothing But a Man (1964) and played a supporting role in the caper film The Thomas Crown Affair (1968). He played John Auston, a confused Marine Lance Corporal, in the 1968 episode, “King of the Hill”, on the first season of Hawaii Five-O.

In 1967 he released a single, “Have You Ever Seen The Blues” / “Have You Dug His Scene” (Chisa Records, CH006).

Kotto was cast as a religious man living in the southwestern desert country in the 1967 episode, “A Man Called Abraham”, on the syndicated anthology series, Death Valley Days, hosted by Robert Taylor. In the story line, Abraham convinces a killer named Cassidy (Rayford Barnes) that Cassidy can change his heart despite past crimes. When Cassidy is sent to the gallows, Abraham provides spiritual solace. Bing Russell also appeared in this segment.

In 1973 he landed the role of the James Bond villain Mr. Big in Live and Let Die, as well as roles in Across 110th Street and Truck Turner. Kotto portrayed Idi Amin in the 1977 television film Raid on Entebbe. He starred as an auto worker in the 1978 film Blue Collar. The following year he played Parker in the sci-fi–horror film Alien. He followed with a supporting role in the 1980 prison drama Brubaker. In 1983, he guest-starred as mobster Charlie “East Side Charlie” Struthers in The A-Team episode “The Out-of-Towners”. In 1987, he appeared in the futuristic sci-fi movie The Running Man, and in 1988, in the action-comedy Midnight Run, in which he portrayed Alonzo Moseley, an FBI agent. A memo from Paramount indicates that Kotto was among those being considered for Jean-Luc Picard in Star Trek: The Next Generation, a role which eventually went to Patrick Stewart.

Kotto portrayed Lieutenant Al Giardello in the long-running television series Homicide: Life on the Street. He has written the book Royalty and also wrote scripts for Homicide. In 2014, he voiced “Parker” for the video game Alien: Isolation, reprising the role he played in the movie Alien in 1979.