She decided to actively pursue acting in the early 1980s, and subsequently, had her breakthrough with her performance as a mobster moll in Prizzi's Honor (1985), also directed by her father, for which she became the third generation of her family to receive an Academy Award, when she won Best Supporting Actress, joining both John and Walter Huston in this recognition.

She won a Golden Globe for playing Carrie Chapman Catt in the cable film Iron Jawed Angels (2004), and a Gracie Award for her portrayal of Eileen Rand in Smash (2012–2013).

[3] Her father's film A Walk with Love and Death (1969), where Huston played the 16-year-old French noblewoman Claudia opposite Assi Dayan, marked her screen debut.

Bob Rafelson's remake The Postman Always Rings Twice (1981), based on the novel by James M. Cain, featured Huston as the fling of a Depression-era drifter, played by Nicholson.

She briefly appeared in the drama Frances (1982) and the mockumentary This Is Spinal Tap (1984) before obtaining a larger role in the science fiction film The Ice Pirates (1984).

Her father cast Huston as Maerose, the daughter of a New York Mafia clan head whose love is scorned by a hit man, in the film adaptation Prizzi's Honor (1985), which also starred Nicholson.

[19] Coppola next cast her as the girlfriend of an army platoon sergeant in Gardens of Stone (1987), a film that dealt with the effect of the Vietnam War on the United States homefront.

"[22] Huston earned a BAFTA nomination for Best Supporting Actress for her portrayal of a flight attendant having an affair with a respected family guy in Woody Allen's dramedy Crimes and Misdemeanors (1989).

In a positive review for the film, Roger Ebert asserted: "Parts, especially the scenes with Huston, are heartwarming in a strange way, because they show one human being accepting the weaknesses of another".

[26] Still wavering, Huston's talent agent Sue Mengers told her bluntly "Anjelica, if Stephen Frears tells you he wants you to shit in the corner, then that's what you must do."

[30] Following a small role in the satire The Player (1992), Huston reunited with Woody Allen on Manhattan Murder Mystery, in which she played the friend of a married couple investigating the death of their neighbor's wife, and also portrayed a mother struggling to parent her autistic child, in the ABC miniseries Family Pictures.

In 1995, Huston portrayed a Cuban refuge attempting to stay in America in the comedy The Perez Family and the former wife of a tormented man (played by Jack Nicholson) in Sean Penn's sophomore directorial effort, the drama The Crossing Guard.

After contemplating the idea of following in her father's footsteps, Huston started to put out "discreet feelers" and pursue material in Hollywood she felt attracted to direct.

[36] Lisa Schwarzbaum from Entertainment Weekly praised her performance as a cruel stepmother: "Huston does a lot of eye narrowing and eyebrow raising while toddling around in an extraordinary selection of extreme headgear, accompanied by her two less-than-self-actualized daughters—the snooty, social-climbing, nasty Marguerite, and the dim, lumpy, secretly nice Jacqueline.

[40] In The Royal Tenenbaums (2001), her first collaboration with director Wes Anderson, Huston took on the role the soft-spoken matriarch of an estranged family of former child prodigies, alongside Gene Hackman, Gwyneth Paltrow, Ben Stiller and Luke Wilson.

In 2002, she portrayed the doctor of an ex-FBI agent (Clint Eastwood) chasing a sadistic killer (Jeff Daniels) in the thriller Blood Work, loosely based on the 1998 novel of the same name by Michael Connelly,[43] as well as the longtime client of a man who runs an exclusive escort service in George Hickenlooper's black comedy The Man from Elysian Fields, with Andy Garcia and Mick Jagger.

[47] In 2004, Huston took on the role of women's suffrage leader Carrie Chapman Catt in the HBO film Iron Jawed Angels, with Hilary Swank, Frances O'Connor and Julia Ormond.

[52] This changed with her third Wes Anderson film, The Darjeeling Limited (2007), in which Huston starred as the mother of three brothers who becomes a nun and moves to a Christian convent in the Himalayas.

[53] Choke (2008), a black comedy directed by Clark Gregg and based on the 2001 novel of the same name by Chuck Palahniuk, featured Huston as the hospitalized mother of a sex addict in Colonial America.

Reviews for the film were mixed, but Empire critic Philip Wilding wrote: "Huston is magnetic as [the] ailing mother Ida, both as a fading invalid or vibrant and deranged in flashback.

The first was that of Miss Battle-Axe, a strict, sadistic schoolteacher who talks with a Scottish accent, in the 3D children's musical adventure comedy Horrid Henry: The Movie, directed by Nick Moore.

[58] Her second performance of 2011 was that of a mother of a man with a malignant cancerous tumor in the drama 50/50, directed by Jonathan Levine and co-starring Joseph Gordon-Levitt and Seth Rogen.

[59] David Schmader, writing in the Stranger, praised the "stellar" cast and felt that Huston "roars back to prominence with a twisty performance as Adam's barely contained mess of a mom".

[62] After her husband's death in 2008, Huston credited Smash —her first regular venture into series television— with coming at a "vital time" and finally filling a void in her life.

[64] Huston subsequently appeared in the second and third seasons of the Amazon Video series Transparent, as Vic, a cisgender woman who forms a connection with Maura, a retired college professor of political science at UCLA.

In the horror comedy The Cleanse (2016), Huston played the director of a secretive self-help program, alongside Johnny Galecki, Anna Friel and Oliver Platt.

"[65] Huston played the Director, a heavily bejeweled Russian ballet instructor, and what Vulture described as a "small but memorable role", in John Wick: Chapter 3 – Parabellum (2019),[10] which made US$326 million worldwide and received positive reviews from critics.

[75] A month later, she met Jack Nicholson at his 36th birthday party, and the pair started an on-again, off-again relationship[76] that lasted until 1990, when the media reported he had fathered a child with Rebecca Broussard.

The letter, signed by over twenty five high-profile individuals from the entertainment business, was addressed to the United Nations Secretary General Ban Ki-moon and urged him to "personally intervene" to secure the release of Nobel Peace Prize recipient Aung San Suu Kyi of Burma.

[82] In December 2012, Huston recorded a public service announcement for PETA urging her colleagues in Hollywood to refrain from using great apes in television, films, and advertisements.