She had an early break when cast as an understudy in the Broadway production of William Inge's The Dark at the Top of the Stairs (1957) directed by Elia Kazan.

Kazan cast Dennis in her first feature film, a small part in Splendor in the Grass (1961), which starred Natalie Wood and Warren Beatty.

The Complaisant Lover (1961–62) by Graham Greene was more successful, running for 101 performances; Michael Redgrave and Googie Withers were also in the cast.

Dennis achieved Broadway fame with her leading role in Herb Gardner's A Thousand Clowns (1962–63), for which she won a Tony award for her performance alongside Jason Robards.

[8] Around this time, Dennis guest-starred on episodes of the TV series Naked City ("Idylls of a Running Back", 1962, "Carrier", 1963), The Fugitive ("The Other Side of the Mountain", 1963), Arrest and Trial ("Somewhat Lower Than the Angels" 1964), and Mr. Broadway ("Don't Mention My Name in Sheboygan", 1964).

[7] Dennis' second film role was as Honey, the fragile, neurotic young wife of George Segal's character, in Who's Afraid of Virginia Woolf?

Directed by Mike Nichols and starring Elizabeth Taylor and Richard Burton, the film was a huge critical and commercial success and Dennis won the Oscar for Best Supporting Actress for her role.

[11] Dennis returned to the stage in a production of The Three Sisters (1966) with Geraldine Page and Kim Stanley that went to London and was filmed.

In his review for The New York Times, Bosley Crowther cited her for "a vivid performance of emotional range and depth … engagingly natural, sensitive, literate and thoroughly moving.

She starred in Sweet November (1968) as a woman who takes multiple lovers, and made a TV version of the play A Hatful of Rain (1968).

She returned to Broadway for How the Other Half Loves (1971) by Alan Ayckbourn, which ran for over 100 performances, then did another TV movie Something Evil (1972), directed by Steven Spielberg, which drew a mixed reception.

In 1974 she played Joan of Arc in the pilot of Witness to Yesterday, Patrick Watson's series of interviews with great figures out of the past.

Dennis was in Mr. Sycamore (1975) with Jason Robards and had a small role in the low-budget horror film God Told Me To (1976) by Larry Cohen.

Her performance in the British comedy Nasty Habits (1977) drew harsh criticism from Vincent Canby in the New York Times.

She appeared on TV in Young People's Specials ("The Trouble with Mother", 1985), The Love Boat ("Roommates/Heartbreaker/Out of the Blue", 1985), Alfred Hitchcock Presents ("Arthur, or the Gigolo", 1985) and The Equalizer ("Out of the Past", 1986).

In motion pictures, she had supporting roles in a 1986 remake of Laughter in the Dark, which was never completed, Woody Allen's Another Woman (1988), and the horror films 976-EVIL (1989) and Parents (1989).

The fact that most of us knew that she was dying of ovarian cancer as she showed us the emotional disintegration of the character made the experience all the more poignant.

In October 1965, her hometown newspaper, The Lincoln Star, published an Associated Press article stating she and Mulligan had married in Connecticut in June of that year.

[18] Dennis' sexual orientation was subjected to public discussion as early as 1968, when the scandal magazine Uncensored ran a story that labeled her a lesbian.