As a bit player for Warner Brothers, Forsythe successfully appeared in several small parts. As a result he was given a small role in Destination Tokyo (1943). Leaving his movie career for service in World War II, he appeared in the U.S. Army Air Forces play and film Winged Victory, then worked with injured soldiers who had developed speech problems.
In 1955, Alfred Hitchcock cast Forsythe in the movie The Trouble with Harry, with Shirley MacLaine in her first movie appearance. The film was unsuccessful at the box office, and Forsythe found high profile movie work harder to find.
Throughout the 1950s, Forsythe successfully appeared in the new medium and regularly on all the networks, especially as a guest star. For example, during this period, Forsythe notably appeared on the popular anthology Alfred Hitchcock Presents in an engaging episode entitled "Premonition" opposite then up-and-coming Cloris Leachman. In 1957, he took a leading role in the situation comedy Bachelor Father for CBS as Bentley Gregg, a playboy lawyer who has to become a father to his niece Kelly (played by Noreen Corcoran), upon the death of her biological parents. The show was an immediate ratings hit and moved to NBC the following season and to ABC in the fall of 1961. He Later starred in The John Forsythe Show on NBC with Guy Marks, Elsa Lanchester, Ann B. Davis, Peggy Lipton, and Forsythe's two young daughters, Page and Brooke. (1965–1966) and To Rome with Love on CBS (1969–1971) with co-star Walter Brennan. Between 1971 and 1977, Forsythe served as narrator on the syndicated nature series, The World of Survival. He was also the announcer for Michelob beer commercials from the 70s through about 1985, notably during the "Weekends were made for Michelob" era.
In 1976, cast in the role of the unseen millionaire and private investigator Charles Townsend in the crime drama Charlie's Angels (1976–1981). Townsend's voice is heard over a speaker phone, instructing the eponymous Angels of their mission for the episode. Following heart problems, Forsythe underwent quadruple bypass surgery in 1979. This was so successful that he safely returned to work on Charlie's Angels, and also appeared in the courtroom drama ...And Justice for All later that year. By 1980, Charlie's Angels was starting to decline in ratings, but Forsythe remained under contract to Aaron Spelling.
In 1981, nearing the end of Charlie's Angels, Forsythe was selected as a last minute replacement for George Peppard in the role of conniving patriarch Blake Carrington in Dynasty (ABC's answer to the highly successful CBS series Dallas). Between 1985 and 1987, Forsythe also appeared as Blake Carrington in the short-lived spin-off series The Colbys.
Dynasty was a hit for Forsythe and proved his most successful role yet. Forsythe and his character became pop culture icons of the 1980s, making him one of Hollywood's leading men and sex symbols. The series explored real-life and fictionalized topics including family feuds, foreign revolutionary gunplay, illegitimate children, sex, drugs, and featured lavish lifestyles and glamorous clothes.
The series reunited Forsythe with Bachelor Father guest star Linda Evans, who had replaced Angie Dickinson to play Blake's compassionate and caring younger wife Krystle. The chemistry between Forsythe and Evans was apparent and as the principal married couple on the show, the two appeared on numerous talk and news magazine shows. During the run of the series, Forsythe, Evans and Collins promoted the Dynasty line of fragrances. Dynasty came to an end in 1989, after a total of nine seasons, with Forsythe being the only actor to appear in all 220 episodes.
Forsythe was nominated five times for the Soap Opera Digest Awards, also winning twice.
In 1992 Forsythe returned to series television starring in Norman Lear's situation comedy, The Powers That Be for NBC. The show was cancelled after only one year.
Forsythe reprised his role as Charlie for the film version of Charlie's Angels (2000) and its sequel Charlie's Angels: Full Throttle (2003), then retired from acting.
On May 2, 2006, Forsythe appeared with Dynasty co-stars Linda Evans, Joan Collins, Pamela Sue Martin, Al Corley, Gordon Thomson and Catherine Oxenberg in Dynasty Reunion: Catfights & Caviar. The one-hour reunion special of the former ABC series aired on CBS.
It was announced that Forsythe was being treated for colorectal cancer on October 13, 2006. He was discharged from the hospital after one month.