Burstyn made her acting debut on Broadway in Fair Game in 1957 before winning the Tony Award for Best Actress in a Play for Same Time, Next Year (1975).

Her other notable films include Harry and Tonto (1974), How to Make an American Quilt (1995), Divine Secrets of the Ya-Ya Sisterhood (2002), W. (2008), Interstellar (2014), The Age of Adaline (2015), and Pieces of a Woman (2020).

Her other Emmy-nominated roles include Pack of Lies (1988), Mrs. Harris (2005), Big Love (2008), Draft Day, Flowers in the Attic (both 2014), and House of Cards (2016).

Starting in the late 1950s, and throughout the 1960s, Burstyn frequently played guest roles on a number of primetime television shows, including Dr. Kildare, 77 Sunset Strip, Ben Casey, Perry Mason, Wagon Train, Gunsmoke, The Big Valley, The Virginian, Laramie and The Time Tunnel.

After many small film roles, Burstyn gained recognition after starring in The Last Picture Show (1971), a coming-of-age story, directed by Peter Bogdanovich and adapted from a semi-autobiographical 1966 novel by Larry McMurtry.

Her co-stars were Max von Sydow, Lee J. Cobb, Kitty Winn, Jack MacGowran, Jason Miller, and Linda Blair.

[19] Film critic Roger Ebert praised Burstyn for her ability to capture MacNeil's "frustration" when her daughter is possessed by an evil spirit.

Her next major role was in Martin Scorsese's romantic drama Alice Doesn't Live Here Anymore (1974) where she played a widowed woman, raising a son and yearning to start a new life for herself as a singer.

[23] Burstyn was also inspired by the works of Betty Friedan and Gloria Steinem, who found that women were searching to "redefine their roles in society".

[23] Burstyn was offered to direct but turned it down to concentrate on her performance, but selected then-newcomer Scorsese as director and recalled the collaboration as "one of the best experiences I've ever had".

[8][23][24] Vincent Canby of The New York Times wrote, "Burstyn never misses the eccentric beat that distinguishes it—that makes Alice such a hugely appealing character who is both banal and very rare".

[32] That year, Burstyn starred in the drama Resurrection, a story about a woman who possesses strange powers after a surviving an automobile crash.

[33][34] In 1981, she starred in the biographical television film The People vs. Jean Harris (1981), based on the real life murder of Herman Tarnower, a well-known cardiologist and author of the best-selling book The Complete Scarsdale Medical Diet.

[35][36] In 1981, Burstyn recorded "The Ballad of the Nazi Soldier's Wife" for Ben Bagley's album Kurt Weill Revisited, Vol.

In addition to television movies, Burstyn appeared in When a Man Loves a Woman (1994) with co-stars Andy Garcia and Meg Ryan.

[44][45] In 1998, Burstyn appeared in Playing By Heart, with co-stars including Sean Connery and Angelina Jolie, a story of eleven ordinary people in Los Angeles who are connected in different ways.

[46][47] Burstyn next found supporting roles in The Spitfire Grill (1996), about a woman starting a new life after being released from prison, and Deceiver (1997), a murder crime drama.

[51] The film is based on the novel of the same name by Hubert Selby Jr, which tells the story of four New Yorkers whose lives are affected by drug addictions.

To prepare for the role, Burstyn had to research troubled women in Brooklyn, "to get their speech patterns and outlook on life—and how narrow that is [...] their life is about getting enough money to put food on the table to feed their children, and that's it".

[52][53] Burstyn and her co-stars Jennifer Connelly, Jared Leto, and Marlon Wayans, found the filming schedule of forty days challenging and intense.

Burstyn appeared in several more films, including Divine Secrets of the Ya-Ya Sisterhood (2002), Brush with Fate (2003) and The Five People You Meet in Heaven (2004).

Burstyn starred in the Broadway production of Martin Tahse's Oldest Living Confederate Widow Tells All, based upon the novel of the same title by Allan Gurganus.

Portraying Dr. Lillian Guzetti, the film is about a scientist (played by Hugh Jackman) struggling with mortality and is seeking a medical breakthrough to save his wife (Rachel Weisz) from cancer.

[70] Burstyn also appeared in the thriller The Wicker Man (2006), a remake of the 1973 British film of the same name, which was a commercial flop and negatively received by critics.

Like its predecessor, the film also garnered negative reviews, with Stephen Holden of The New York Times writing, "a film of tightly assembled bits and pieces that don't fit comfortably together despite clever dashes of magical realism connecting past and present... it leaves you frustrated by its failure to braid subplots and characters into a gripping narrative".

[77] In 2009, Burstyn won the Primetime Emmy Award for Outstanding Guest Actress in a Drama Series for her portrayal of the bipolar estranged mother of Detective Elliot Stabler on NBC's Law & Order: Special Victims Unit.

In 2015, Burstyn played Flemming, the daughter of Blake Lively's immortal character in the romantic fantasy film The Age of Adaline.

[89] Burstyn served as an executive producer for Peter Livolsi's film The House of Tomorrow (2017), about her friend R. Buckminster Fuller, in which she also starred.

She described Neil Burstyn as "charming and funny and bright and talented and eccentric", but schizophrenia made him violent and he eventually left her.

Burstyn completed the triple crown more than 30 years later, with a Primetime Emmy Award for her guest starring role on Law and Order: SVU (2009).