He was best known for his role as John "Plato" Crawford in the drama film Rebel Without a Cause (1955), which earned him a nomination for the Academy Award for Best Supporting Actor at age 17, making him the fifth-youngest nominee in the category.

Mineo also starred in films such as Crime in the Streets, Giant (both 1956), Exodus (1960), for which he won a Golden Globe and received a second Academy Award nomination, The Longest Day (1962), John Ford's final western Cheyenne Autumn (1964) and Escape from the Planet of the Apes (1971).

He attended the Quintano School for Young Professionals[4][5] and was one of the few Italian-American actors of his era to keep his surname, saying he was proud of his heritage and identity.

[1] On May 8, 1954, Mineo portrayed the Page (lip-synching to the voice of mezzo-soprano Carol Jones) in the NBC Opera Theatre's production of Richard Strauss's Salome (in English translation), set to Oscar Wilde's play.

[9][10] Elaine Malbin performed the title role, and Peter Herman Adler conducted Kirk Browning's production.

Mineo made several television appearances before making his screen debut in the Joseph Pevney film Six Bridges to Cross (1955).

[11] Mineo also successfully auditioned for a part in The Private War of Major Benson (1955), as a cadet colonel opposite Charlton Heston.

[8] Mineo's performance resulted in an Academy Award nomination for Best Supporting Actor and he became the fifth-youngest nominee in the category, at the age of 17.

[33][non-primary source needed] Mineo's last role in a motion picture was a small part in the film Escape from the Planet of the Apes (1971);[34] he played the chimpanzee Dr. Milo.

[35] Muriel Costa-Greenspon portrayed the title character, Madame Flora, and Mineo played the mute, Toby.

In 1975, Mineo appeared as Rachman Habib, the assistant to a murderous consular head (portrayed by Hector Elizondo) of a Middle Eastern country, in the Columbo episode "A Case of Immunity," on NBC-TV.

Your Cat Is Dead in San Francisco, Mineo received substantial publicity from many positive reviews; he moved to Los Angeles along with the play.

[41] Mineo met English-born actress Jill Haworth on the set of the film Exodus in 1960, in which they portrayed young lovers.

[42][43] Mineo expressed disapproval of Haworth's brief relationship with television producer Aaron Spelling, who was 22 years older than she.

"[42] At the time of his death, he was in a six-year relationship with actor and retired acting coach Courtney Burr III.

[45] Lionel Ray Williams, a young pizza delivery man with a long criminal record, was convicted and sentenced in March 1979 to 51 years in prison for killing Mineo and also for committing ten robberies.