In 1957, she headed west to study at the Pasadena Playhouse where she made her stage debut the following year in "Look Back in Anger". Knight was put under contract by Warner Bros. and the petite blonde earned critical acclaim and a Best Supporting Actress Oscar nomination as an Oklahoman in love with a Jew in the screen adaptation of William Inge's "The Dark at the Top of the Stairs" (1960). She picked up a second nod in the same category as Heavenly Finley, the woman seduced and abandoned by Chance Wayne, in "Sweet Bird of Youth" (1962). In "The Group" (1966), her character found seeming happiness with James Broderick while later that same year she delivered a strong turn as a sluttish white woman who confronts a young black male passenger in "The Dutchman". After a strong turn as a pregnant woman who runs off with a football player in Francis Ford Coppola's "The Rain People" (1969), Knight moved to England with her second husband, British playwright John Hopkins and did not act on screen for five years, returning in "Juggernaut" (1974). Her subsequent film roles have generally cast her in maternal roles as in "Endless Love" (1981), "Stuart Saves His Family" (1995) and "As Good As It Gets" (1997).
While she found almost immediate success in films, Knight has a stated preference for stage work. Spurning an offer to play Ophelia to Richard Burton's "Hamlet", she opted to co-star with Geraldine Page and Kim Stanley in an Actors Studio production of Chekhov's "Three Sisters" (1964). She acquired a Tony as Featured Actress in a Play for her turn as a floozy in "Kennedy's Children" (1975) and has appeared in several classics including twice playing Blanche in "A Streetcar Named Desire", Lola in "Come Back, Little Sheba" and Amanda Wingfield in "The Glass Menagerie". More recently, Knight returned to Broadway and netted a Tony nomination for her turn as a woman who refuses to accept that her son committed suicide in Horton Foote's Pulitzer-winning "The Young Man From Atlanta" in 1997.
The small screen has also provided the actress with challenging roles. She made her first appearance in the medium in a live broadcast in 1959 and amassed numerous guest credits in the 60s and 70s. Knight co-starred opposite Jason Robards in a "Hallmark Hall of Fame" presentation of "The Country Girl" (NBC, 1974) and Alan Arkin in the above average CBS movie "The Defection of Simas Kudirka" (1978). She offered a strong turn and earned her first Emmy nomination as a concentration camp inmate in the acclaimed "Playing for Time" (CBS, 1980) before picking up the award for a guest appearance as the mother of Mel Harris' Hope in a 1987 episode of ABC's "thirtysomething".
Knight had her first regular series role in the short-lived 1993 CBS drama "Angel Falls". At the 1995 Emmy Awards, she picked up two statuettes, one for her guest appearance as the mother of a murder victim in an episode of "NYPD Blue" and the second as day care center owner Peggy Buckley who was accused of and tried for child molestation in the fact-based HBO drama "Indictment: The McMartin Trial". Knight has continued to be a powerful presence in the medium, offering effective supporting turns in such made-for-television fare as "Stolen Memories: Secrets From the Rose Garden" (Family Channel, 1996), "Mary & Tim" (CBS, 1996) and "The Wedding" (ABC, 1998). She returned to regular series work cast as the mother of the titular "Maggie Winters" in the short-lived 1998 CBS sitcom starring Faith Ford. The actress's schedule remained packed with continual roles in feature films--including "Angel Eyes" (2001), "The Salton Sea" (2002) and "The Divine Secrets of the Ya-Ya Sisterhood" (2002).
Knight became a regular fixture on the small screen with guest appearances on such series as "Ally McBeal," "ER," "Law & Order: Special Victims Unit," "Crossing Jordan," and "Cold Case" and "House," and in 2005 she began a recurring stint on "Desperate Housewives" as Phyllis Van De Kamp, the meddling mother-in-law of tightly wound Bree (Marcia Cross).