She was born in 1944 in Brooklyn and moved with her parents as a child to Weston, Connecticut and graduated from Staples High School in Westport in 1962. She then attended the Mount Holyoke College in South Hadley, Massachusetts in 1966, where she graduated and then moved the same year to England to study at the Ruskin School of Drawing and Fine Art at the University of Oxford. At Oxford she met fellow student Giles Trentham; they married in 1967 and she retained his name after their divorce in 1970.

In the early 1970s Trentham worked as a model in London. Her photo appeared several times on the cover pages of British magazines including Seventeen and Vogue.

in 1972 she landed a supporting role alongside Shirley MacLaine, Perry King and David Elliott in Waris Hussein's horror thriller The Possession of Joel Delaney. She then moved to Los Angeles to pursue her acting career. She starred in Norman Jewison's science fiction classic Rollerball alongside James Caan, John Houseman, Maud Adams and John Beck. In 1976 she was seen in the action drama Sky Riders with James Coburn and Susannah York. In the same year she also had a cameo in the British-German television series The Girl from Outer Space with Pierre Brice. In 1978, she appeared in the produced-for-television horror film Wolf Moon and 1979 in an episode of the adventure series A Man Called Sloane.

In 1980, while working in Los Angeles as a reporter and Producer of Those Amazing Animals, she met British actor and Comedian John Cleese at a Monty Python performance. They married in 1981; their daughter Camilla was born in 1984. In 1990, the couple separated but remained on good terms.

During her marriage to Cleese her love for art was reawakened and she began a third career as a Painter, her preferred medium being oil paint. In 1993 she moved to Chicago, where she met the Lawyer George Covington. The two married in 1998 and lived in Lake Bluff, Illinois. She built up an art studio which became the meeting place and source of inspiration for local artists. She was also co-founder of a local organization for artists. She was a member of the Art Association of Jackson Hole, and organized events and art fairs there.

Barbara Trentham died on August 2, 2013 at Northwestern Memorial Hospital in Chicago, aged 68, from complications from leukemia.