[9] Clayburgh began acting as a student in summer stock and, after graduating, joined the Charles Street Repertory Theater in Boston, where she met another up-and-coming actor and future Academy Award-winning star, Al Pacino, in 1967.

[10] In 1968, Clayburgh debuted off-Broadway in the double bill of Israel Horovitz's The Indian Wants the Bronx and It's Called the Sugar Plum, also starring Pacino.

Clayburgh and Pacino were cast in "Deadly Circle of Violence", an episode of the ABC television series NYPD, premiering November 12, 1968.

[11] She eventually made her Broadway debut in 1968 in The Sudden and Accidental Re-Education of Horse Johnson, co-starring Jack Klugman, which ran for 5 performances.

The film focuses on a soon-to-be groom and his interactions with various relatives of his fiancée and members of the wedding party; Clayburgh played the bride-to-be.

In his review from The New York Times, Howard Thompson wrote, "As the harassed engaged couple, two newcomers, Charles Pfluger and Jill Clayburgh, are as appealing as they can be.

She then went on to play Desdemona opposite James Earl Jones in the 1971 production of Othello in Los Angeles, and had another Broadway success with Pippin (1972–75), which ran for 1,944 performances.

After guest-starring on an episode of The Snoop Sisters, Clayburgh played Ryan O'Neal's ex-wife in The Thief Who Came to Dinner (1973) and starred in a TV pilot that was not picked up, Going Places (1973).

"[18][19] Vincent Canby of The New York Times suggested that her performance "comes off better" than Brolin's Gable, as "she appears to be creating a character whenever the fearfully bad screenplay allows it."

Despite this, he felt both actors were miscast as the famous couple, writing further, "Miss Clayburgh could be an interesting actress, but there are always problems when small performers try to portray the kind of giant legends that Gable and Lombard were.

Also in 1976, she had her first big box office success playing the love interest of Gene Wilder's character in the comedy-mystery Silver Streak, also starring Richard Pryor.

Critics felt Clayburgh had little to do in Silver Streak, and The New York Times called her "an actress of too much intelligence to be able to fake identification with a role that is essentially that of a liberated ingenue.

Vincent Canby liked her performance, writing, "Miss Clayburgh, who's been asked to play zany heroines in Gable and Lombard and Silver Streak by people who failed to provide her with material, has much better luck this time.

"[22][23] Both Semi-Tough and Silver Streak earned her a reputation "as a popular modern stylist of screwball comedy" and The Guardian noted how Clayburgh "had the kind of warmth and witty sophistication barely seen in Hollywood since Carole Lombard and Jean Arthur".

In what would be her career-defining role, Clayburgh was cast as Erica, the courageous abandoned wife who struggles with her new 'single' identity after her stockbroker husband leaves her for a younger woman.

[25] Clayburgh's performance garnered some of the best reviews of her career: Roger Ebert called the film "a journey that Mazursky makes into one of the funniest, truest, sometimes most heartbreaking movies I've ever seen.

She's letting us see and experience things that many actresses simply couldn't reveal" while The New York Times wrote, "Miss Clayburgh is nothing less than extraordinary in what is the performance of the year to date.

Writing for The New Yorker, veteran critic Pauline Kael noted: Jill Clayburgh has a cracked, warbly voice -- a modern polluted-city huskiness.

"[30] Despite the film's controversy, Clayburgh's performance as a manipulative opera singer was generally praised: Critic Richard Brody called it "her most extravagant role" and a review in The New York Times felt she was "extraordinary under impossible circumstances.

"[31][32] Also, in the London Review of Books, Angela Carter wrote, "Jill Clayburgh, seizing by the throat the opportunity of working with a great European director, gives a bravura performance: she is like the life force in person".

"[29] As a nursery-school teacher who falls reluctantly in love with Reynolds’s divorced character, her performance was lauded by The New York Times: "Miss Clayburgh delivers a particularly sharp characterization that's letter-perfect during the first part of the story and unconvincing in the second, through no fault of her own.

"[35] The film received negative reviews, but Janet Maslin of The New York Times liked Clayburgh's performance and wrote that she played her high-powered career woman "earnestly and vigorously.

[14] Alongside then-rising stars Raúl Julia and Frank Langella, Clayburgh returned to Broadway for a revival of Noël Coward's Design for Living (1984–85), directed by George C. Scott, which ran for 245 performances.

A review in People magazine felt Clayburgh "[did] her best as the footloose mother" in Rich in Love, while Roger Ebert praised her casting in Naked in New York as "exactly on target".

[56] After appearing in My Little Assassin (1999) and The Only Living Boy in New York (2000), she had her first prominent lead role since Hanna K. and Shy People in Eric Schaeffer's comedy Never Again (2001).

[61] Variety critic David Rooney praised Clayburgh's "wisdom and quiet humor while refusing to define Hannah’s questionable behavior and convictions as right or wrong, sound or unsound" and her "embrace of the woman’s uncertainties, mak[ing] her all the more human.

[63] Still, Clayburgh's performance drew praise and the New York Times critic Ben Brantley lauded "her winning way with dialogue that can make synthetic one-liners sound like filigree epigrams.

"[64] She returned to the screen that same year as a therapist's eccentric wife in Ryan Murphy's all-star ensemble dramedy Running with Scissors, an autobiographical tale of teenage angst and dysfunction based on the book by Augusten Burroughs; also starring Annette Bening, Gwyneth Paltrow and Evan Rachel Wood, Clayburgh's supporting performance earned her a Best Supporting Actress nomination by the St. Louis Gateway Film Critics Association.

By the end of 2006, Clayburgh played a wistful eccentric in what was her last stage appearance, The Clean House (2006–07) on off-Broadway, and was praised for her "goofy lightness" by The Post Gazette.

[65] During 2007–2009, Clayburgh appeared in the ABC television series Dirty Sexy Money, playing the wealthy socialite Letitia Darling.