Born to an Italian-American family (his grandparents emigrated from Melfi, Basilicata, in 1890), and raised by his mother and aunt, he adopted his mother's maiden name Franciosa as his professional name.

In 1948, Franciosa joined the Cherry Lane Theatre Group off Broadway (at the same time as Actress Beatrice Arthur). Within two years, he had been accepted as a member of the Actors Studio, which would prove an invaluable resource going forward but it would be a few years more before Franciosa could make a living from acting. In the meantime, he worked a variety of jobs which included being a waiter, dishwasher, day laborer, and messenger boy. Several years later he garnered rave reviews and a Tony Award nomination for his Broadway performance of the play A Hatful of Rain.

Franciosa was married four times, and had three children. His first wife, Beatrice Bakalyar, was a Writer. They were married from 1952 to 1957. The marriage ended in divorce. His second wife was Oscar-winning Actress Shelley Winters; they were married from May 4, 1957 until their divorce in 1960; they had no children. Her death preceded his by five days.

In 1958, Franciosa had been nominated for an Academy Award for his role as Polo Pope in the film version of A Hatful of Rain (1957), opposite Eva Marie Saint and Don Murray as his brother, Johnny, a morphine addict.

Billed as "Anthony Franciosa," he won the 1960 Golden Globe Award for Best Actor – Motion Picture Drama for the role "Sam Lawson" in Career (1959), opposite Dean Martin and Shirley MacLaine. He had won the Globe competing with actors Charlton Heston in Ben-Hur, Richard Burton in Look Back in Anger, Fredric March in Middle of the Night and Joseph Schildkraut as Otto Frank in The Diary of Anne Frank.

He guest-starred in the television series The Greatest Show on Earth, Jack Palance's circus drama, which aired on ABC from 1963–1964. That same season, he appeared in the ABC medical drama about psychiatry, Breaking Point.

His last wife (from November 27, 1970 until his death in 2006) was Rita Theil, by whom he had two sons, Marco and Christopher. Christopher Franciosa is an actor. Marco Franciosa is an organic farmer.

Eager to act in any medium, he became a series lead in the sitcom Valentine's Day and drama TV series The Name of the Game (and its pilot TV-movie Fame Is the Name of the Game), as lead role of charismatic but doggedly determined star reporter Jeff Dillon, alternating the regular lead spot with Gene Barry and Robert Stack. He was fired from the series because of his temper. He had a further alternating lead role, this time alongside Hugh O'Brian and Doug McClure, as agent Nick Bianco in Search, and then on his own in Matt Helm, a spinoff of the spy-spoof films that starred Dean Martin. He also played roles in all-star television miniseries, such as Aspen (1977) and Wheels (1978).

In the 1980s, he starred in the Aaron Spelling-produced series Finder of Lost Loves. Franciosa also made notable guest star appearances as a villain in the Western series The Virginian (episode "Holocaust," aka "The Shiloh Years") and later The Men from Shiloh, plus was star of the Theatre of Stars episode "A Case of Armed Robbery" convincingly playing a man with feelings of alienation from a society driven to crime. In the 1985 revival of The Twilight Zone, he appeared in the third-season episode "Crazy As a Soup Sandwich," playing a gangster who is revealed to be the ultimate demon.

Franciosa's final film was City Hall, a 1996 drama starring Al Pacino and John Cusack, in which he portrayed a New York City crime boss.

On January 19, 2006, Franciosa died at age 77 at UCLA Medical Center in Los Angeles, California after suffering a massive stroke. His death followed that of his ex-wife Shelley Winters by five days (Franciosa suffered the stroke the day Winters died, January 14). He is survived by his wife, Rita, his children, Nina, Christopher, and Marco and his grandchildren, Ruby, Cassius, Alistar, and Rye Franciosa.