Among Topol's earliest film appearances was the lead role in the 1964 film Sallah Shabati by Ephraim Kishon — a play, later adapted for film, depicting the hardships of a Mizrachi Jewish immigrant family in Israel of the early 1960s. The film was nominated for the Academy Award for Best Foreign Language Film and earned the actor the Golden Globe Award for New Star of the Year - Actor. In 1966, Topol made his first English-language screen appearance as Abou Ibn Kaqden in the big-budget Mickey Marcus biopic Cast a Giant Shadow.
He came to greatest prominence in the role of Tevye the milkman in the long-running musical show Fiddler on the Roof, at Her Majesty's Theatre. After scoring a major success on the West End stage, he later starred in the 1971 film version.
In 1972, Topol won a Golden Globe Award and was nominated for a Best Actor Oscar for his performance in the film. He was on active service with the Israeli Army at the time, but was granted permission to attend the awards ceremonies.
In 1976, Topol originated the leading role of the baker, Aimable, in the new musical "The Baker's Wife", but was fired after eight months by producer David Merrick. In her autobiography, "Patti LuPone: A Memoir", his co-star in the production relayed that Topol behaved unprofessionally in front of paying audiences, sometimes speaking gibberish instead of his lines, and other times responding to the director's instructions by grossly overacting on purpose. Her account was echoed by the show's composer, Stephen Schwartz, in the book "Defying Gravity: The Creative Career of Stephen Schwartz, From Godspell to Wicked", in which he claimed that Topol's unprofessional behavior greatly disturbed the cast and directors and resulted in the production not reaching Broadway as planned.
Some of Topol's other notable appearances were in Galileo (1975), Flash Gordon (1980), and as Milos Columbo in James Bond movie For Your Eyes Only (1981).
In 1983, he reprised the role of Tevye in a London revival of Fiddler on the Roof. In the late 1980s, he played the role in a touring United States production. He was by now the approximate age of the character, and in fact the actress playing his wife, Golde, in that production Rosalind Harris had played his eldest daughter, Tzeitel, in the film. In 1990, he again played the part in a Broadway revival of Fiddler, and was nominated for 1991 a Tony Award for Best Performance by a Leading Actor in a Musical, losing to Jonathan Pryce. He played the part again in a 1994 London revival, which became a touring production. He has since played the part in various productions including stages in Europe, Australia and Japan. His most recent film roles were in Left Luggage (1998) in the role of Mr. Apfelschnitt, and Time Elevator (1998) as Shalem.
In 2005, he was voted the 90th-greatest Israeli of all time, in a poll by the Israeli news website Ynet to determine whom the general public considered the 200 Greatest Israelis.
In November 2005, Topol had a two-month season once again playing Tevye in Fiddler On the Roof at Capitol Theatre in Sydney, Australia and in April 2007, played the role in Wellington, New Zealand. In September 2008, Topol played the part of Honore in Gigi at the Open Air Theatre in Regent's Park, London.
On January 20, 2009, Topol began a farewell tour of Fiddler on the Roof as Tevye, opening in Wilmington, Delaware. He was forced to withdraw from the tour owing to a shoulder injury, and made his last appearance as Tevye in Boston, Massachusetts on November 15, 2009. (Theodore Bikel and Harvey Fierstein, both of whom have portrayed Tevye on Broadway, replaced him in scheduled appearances.)