Frank Joseph Perry Jr. was born in New York City, to stockbroker Frank Joseph Perry Sr. (March 21, 1905 — December 9, 1969) and Pauline E. Schwab, who worked at Alcoholics Anonymous. Pauline was also a niece of Charles M. Schwab, who founded the Bethlehem Steel Corporation. As a teenager, Frank Jr. began pursuing his interest in the theater with a job as a parking lot attendant for the Westport Country Playhouse in nearby Westport, Connecticut. He attended the University of Miami. Frank also studied under Lee Strasberg in New York. He produced several plays at Westport Country Playhouse and then turned for a time to producing television documentaries.

A veteran of the Korean War, he returned to the entertainment industry after being discharged and made his directorial debut in 1962 with the low-budget drama film David and Lisa. Based on the novel by Theodore Isaac Rubin, the screenplay was written by his wife, Eleanor Rosenfeld, who received a nomination for an Academy Award for Writing Adapted Screenplay. A character study of two emotionally disturbed teenagers, the film was successful at the box office and met with much critical acclaim, earning him a nomination for an Academy Award for Directing. Both Perrys would eventually join the select group of non-actors awarded membership in Actors Studio. Perry went on to direct and produce a number of films, including The Swimmer (1968) based on a John Cheever story, Last Summer (1969), and Trilogy (1969), written by Truman Capote.

Perry is known for his character studies involving a dysfunctional family, such as that in his wife's script of the Sue Kaufman novel Diary of a Mad Housewife (1970). That film earned a Best Actress Oscar nomination for Carrie Snodgress, and Play It As It Lays (1972), starring Tuesday Weld, brought her a Golden Globe Best Actress nomination. Both of these films Perry produced and directed, though he is probably best remembered for directing the notorious 1981 low-budget biographical drama Mommie Dearest, an adaptation of a biography by Actress Joan Crawford's adoptive daughter, which portrayed the famous movie star as a crazed, sadistic tyrant who cared more about her acting career than her adopted children. The film became a cult classic despite mixed reviews from critics; it also won the razzie award for worst picture and Frank Perry was nominated for worst Director.

In 1958, Frank married his first wife Eleanor, who was 15 years his senior. Perry and Eleanor collaborated on many screen projects, including screenwriting the Academy Award-nominated 1962 "David & Lisa". They divorced in 1971 on grounds of incompatibility. She later wrote the book Blue Pages about her relationship with Frank. The union produced no children. Eleanor Perry died of cancer a decade later, at age 66. In 1977, Perry married his second wife, Barbara Goldsmith, founding Editor of New York magazine and book author (Little Gloria … Happy at Last), whom he divorced in 1992. Soon after, he married his Aspen ski instructor, 22-year-younger Virginia Brush Ford, on June 15, 1992. His sister is pastor Mary Christine Perry, the wife of pastor Maurice Keith Hudson and mother of Singers Katy Perry and David Hudson.

Perry died of prostate cancer on August 29, 1995, eight days after his 65th birthday, at Memorial Sloan-Kettering Cancer Center in Manhattan. His final film, 1992's On the Bridge, is an autobiographical documentary dealing with the illness. His ashes were scattered on the mountains of Aspen, Colorado, where he lived the last three years of his life.