During Thanksgiving 1960, while vacationing in Los Angeles with a group of friends, Tiffin visited the Paramount Pictures lot and was spotted by producer Hal B. Wallis, who persuaded her, despite her initial reluctance, to take a screen test. As a result, she was cast in the film version of Summer and Smoke, directed by Peter Glenville. Shortly later, she signed a 7-years contract with 20th Century-Fox, which contemplated one picture per year for $8,000, plus the option to cast her in three additional films, and a contract with Hal B. Wallis.
Tiffin next played the daughter of James Cagney's boss in the comedy One, Two, Three (1961). The film's director Billy Wilder had spotted her in an ad in The New York Times, and cast her immediately after her audition. He called her "the biggest find since Audrey Hepburn". She earned a Golden Globe nomination for each of her first two films,
She won the leading role in the Twentieth Century-Fox musical remake State Fair (1962), in which she played Bobby Darin's love interest. Later, she was attached to a series of projects that never got off the ground, including an adaptation of Camelot with Laurence Olivier, and the main role in A Rage to Live, which was postponed and eventually shot in 1965 with Suzanne Pleshette; she was also offered the role of Tamiko in John Sturges' A Girl Named Tamiko, was considered for Tippi Hedren's role in Hitchcock's The Birds, and turned down a role in the Elvis Presley vehicle Girls! Girls! Girls!. She eventually was chosen as one of the three leads in MGM's comedy Come Fly with Me (1963).
Tiffin later studied at New York's Columbia University and continued to model. She made her television debut as a "Special Guest Star" on The Girl from Little Egypt, an episode of The Fugitive, and filmed a television pilot for Fox titled Three in Manhattan that did not materialize into a series. Tiffin agreed to take part only after Fox assured her she would be released from her contract after one more film. The pilot, which also starred Julie Newmar, Thelma Ritter's daughter Monica Moran and Jody McCrea, was eventually broadcast as an episode of the anthology series Vacation Playhouse.
Following her TV work, Tiffin refused the female lead in Fun in Acapulco, and was considered for the Sandra Dee role in Take Her, She's Mine and for the Yvette Mimieux role in Toys in the Attic. She made two films with James Darren, both aimed at teen audiences: For Those Who Think Young (1964) and The Lively Set (1964). Fox cast her in The Pleasure Seekers (1964), a remake of Three Coins in the Fountain (1954). She later co-starred with Burt Lancaster in the 1965 Western The Hallelujah Trail.
After a series of professional disappointments, having failed to secure several roles she was considered for and deeply wanted, notably in The Great Race, Who's Afraid of Virginia Woolf?, The Collector, and The Group, Tiffin appeared in her most successful film, Harper (1966) alongside Paul Newman.
