She debuted on Broadway in 1957 and, in 1975, won a Tony Award for Best Actress in a Play for her performance in "Same Time, Next Year." In 1990 she won the Sarah Siddons Award for her work in Chicago theatre. Until 1970, she was credited as "Ellen McRae" in nearly all her film and TV appearances.

Burstyn won the Academy Award for Best Actress in 1974 for her performance in the movie Alice Doesn't Live Here Anymore. She received her first Oscar nomination for Best Supporting Actress in 1971 for the film The Last Picture Show, and was subsequently nominated for Best Actress in 1973 for the horror movie The Exorcist, in 1978 for Same Time, Next Year, in 1980 for Resurrection, and for Requiem for a Dream in 2000.

She appeared in many television shows of the 1960s, including guest appearances on Perry Mason, Maverick, Wagon Train, 77 Sunset Strip, The Big Valley and Gunsmoke. She hosted Saturday Night Live in 1980. In 1986, she had her own sitcom, The Ellen Burstyn Show with Megan Mullally as her daughter and Elaine Stritch as her mother. It was cancelled after one season. From 2000 to 2002, Burstyn appeared in the CBS television drama That's Life. In 2006, she starred as a bishop in the controversial NBC comedy-drama The Book of Daniel.

Burstyn last appeared in The Fountain, directed by Darren Aronofsky, with whom she worked in Requiem for a Dream.

Burstyn was nominated for an Emmy Award for Outstanding Actress in a Miniseries or Special, for the TV movie The People vs. Jean Harris (1981) and again for another TV movie, Pack of Lies (1987).

In 2006, she was nominated for an Emmy for Outstanding Supporting Actress in a Miniseries or Special for HBO's Mrs Harris as Dr. Tarnower's "Ex-Lover #3." (She had played the title character in The People vs Mrs Jean Harris.) She was nominated for a performance that consisted of 14 seconds of screen time, two lines of dialogue and a total of 38 words. This is the shortest nominated performance in the history of the Emmy Awards.

Soon after the nominations were announced, an outcry ensued from the press and the public regarding the worthiness of the nomination. One explanation was that people were honoring Burstyn for her nominated but non-winning performance from the first Harris telefilm. A more popular accusation was that the nominating committee was either confused in their recollection, or merely "threw in" her name from sheer recognition and assumption of a worthy performance without actually having viewed it.

The Academy of Television Arts & Sciences initially insisted that "based on the popular vote, this is a legitimate nomination." Meanwhile, HBO deflected the blame for submitting the nomination to the movie production company. Burstyn's own reaction ranged from initial silence to:

I thought it was fabulous. My next ambition is to get nominated for seven seconds, and ultimately I want to be nominated for a picture in which I don't even appear.

to this final quote:

This doesn't have anything to do with me. I don't even want to know about this. You people work it out yourself.

Ultimately, Kelly Macdonald, who starred in The Girl in the Cafe, won the award. Neither Burstyn or her costar Cloris Leachman won. In March 2007, the Academy officially announced that eligibility for a Primetime Emmy Award in any of the long-form supporting-actor categories required nominees to appear on-screen in at least 10 percent of the project (9 minutes in a typical 90-minute telefilm).

Many continue to cite this incident to illustrate the lack of integrity in the increasingly expansive process of Emmy Award nominations, where name and role misrecognition have played an increasingly visible role.