Perkins made his film debut in The Actress (1953). He received the Golden Globe Award for New Star of the Year – Actor and an Academy Award nomination for his second film, Friendly Persuasion (1956). The tall (6’2″, 188 cm) Perkins also portrayed the troubled former Boston Red Sox baseball player Jimmy Piersall in the 1957 true story Fear Strikes Out.  Following this, he released three pop music albums in 1957 and 1958 on Epic and RCA as “Tony Perkins”. His single “Moon-Light Swim” was a hit in the United States, peaking at #24 on the Billboard Hot 100 in 1957. He starred with Shirley Booth and Shirley MacLaine in the film The Matchmaker (1958).

A life member of The Actors Studio, Perkins also acted in theater. In 1958, he was nominated for a Tony Award for Best Actor in a Play for his performance in Look Homeward, Angel on Broadway. During this time he also co-starred in Desire Under the Elms (1958) with Sophia Loren, and played a basketball star in the romantic comedy Tall Story (1960) opposite Jane Fonda.

Perkins was cast as Norman Bates in the Alfred Hitchcock-directed film Psycho (1960). The film was a critical and commercial success, and gained Perkins international fame for his performance as the homicidal owner of the Bates Motel. Perkins’ performance gained him the Best Actor Award from the International Board of Motion Picture Reviewers. In 1961, Perkins received considerable critical acclaim for his performance in the film Goodbye Again, opposite Ingrid Bergman, a performance which won him the Best Actor Award at the 1961 Cannes Film Festival.

After that came a successful career in Europe, including the role of Joseph K. in Orson Welles’ 1962 adaptation of Kafka’s The Trial (both 1962). Upon returning to America, he took the role of a disturbed young murderer in Pretty Poison (1968) opposite Tuesday Weld. He also played Chaplain Tappman in Catch-22 (1970).  Perkins co-wrote, with composer/lyricist Stephen Sondheim, the screenplay for the 1973 film The Last of Sheila, for which they received a 1974 Edgar Award from the Mystery Writers of America for Best Motion Picture Screenplay.

In 1972, he appeared in The Life and Times of Judge Roy Bean, and was one of the many stars featured in the 1974 hit Murder on the Orient Express. In 1974, Perkins played the lead role in the romantic drama Lovin’ Molly with Blythe Danner and Susan Sarandon. Perkins also hosted television’s Saturday Night Live in 1976 and was featured in his only science fiction film, the box office-smash and space opus, Walt Disney’s The Black Hole, in 1979.  His Broadway credits also included the 1967 Neil Simon comedy The Star-Spangled Girl, the Frank Loesser musical Greenwillow (1960), for which he was nominated for another Tony Award for Best Actor in a Musical and Bernard Slade’s 1979 play Romantic Comedy opposite Mia Farrow.

Perkins reprised the role of Norman Bates in three sequels to Psycho. The first, Psycho II (1983), was a box office success more than 20 years after the original film. He then starred in and directed Psycho III (for which he was nominated for a Saturn Award for Best Actor) in 1986, but refused to reprise his role as Bates in the failed television pilot Bates Motel, famously boycotting the project in a very ardent, and well-received, oppositional public campaign. He did play Bates in the following made-for-cable film Psycho IV: The Beginning in 1990, over which he had much creative control, although he was turned down for director. He directed a film in 1988 called Lucky Stiff.

Perkins has a star on the Hollywood Walk of Fame, an honor he received for his influential and exceptional contributions to the motion picture industry. It is located at 6801 Hollywood Boulevard in Hollywood, California.  In 1991, Perkins was honored with the Donostia Lifetime Achievement Award at the San Sebastián International Film Festival.

Although he was fighting AIDS, the actor appeared in eight television productions between 1990 and 1992, including Daughter of Darkness (1990) with Mia Sara and The Naked Target (1992) with Roddy McDowall. He made his final appearance in In Deep Woods (1992) with Rosanna Arquette.  Perkins had agreed to provide the voice for the role of the dentist, Dr. Wolfe, in The Simpsons episode “Last Exit to Springfield” after Anthony Hopkins and Clint Eastwood both turned the role down, but he died before the part could be recorded. In the end, the character was voiced by Simpsons regular Hank Azaria.

On August 9, 1973, Perkins married photographer Berinthia “Berry” Berenson. They had two sons: actor Oz Perkins (b. February 2, 1974), and musician Elvis Perkins (b. February 9, 1976).  He once said he felt too nervous around women, and resisted actresses Jane Fonda and Brigitte Bardot, who had tried to seduce him during his youth. He was a very shy actor, especially in women’s company. According to an unauthorized biography by Charles Winecoff, he had affairs with Christopher Makos, actor Tab Hunter, dancer Rudolf Nureyev, composer/lyricist Stephen Sondheim,Nick Adams (The Rebel) and dancer-choreographer Grover Dale prior to marrying Berenson. He had his first intimate heterosexual experience at the age of 39 while working on the 1972 film The Life and Times of Judge Roy Bean with an actress who also appeared in the film. Perkins declined to identify the actress, but “other sources” have identified her as Victoria Principal. Principal confirmed this in a People magazine article about Perkins.  Perkins died at his Hollywood Hills home on September 12, 1992, from AIDS-related pneumonia.