In 1989, Weaver won two Golden Globes and two simultaneous Oscar nominations for her roles as Dian Fossey in Gorillas in the Mist (1988) and a young associate in Working Girl (1988).

Her other film roles include The Year of Living Dangerously (1982), Copycat (1995), Galaxy Quest (1999), The Village (2004), Vantage Point (2008), Chappie (2015), and A Monster Calls (2016).

On stage, Weaver's Broadway performances include The Constant Wife (1975), Hurlyburly (1984), and Vanya and Sonia and Masha and Spike (2013).

[16] Known for her height, she reportedly reached 180 cm (5 ft 11 in) by the age of 11, which had a negative impact on her self-esteem; she recalled feeling like "a giant spider" and never having "the confidence to ever think [she] could act".

She performed with a group in Palo Alto named The Company,[18] doing Shakespeare plays and "commedia dell'arte in a covered wagon" around the Bay Area,[18] the nature of which she considered "outrageous".

She "dressed like an elf and lived in a tree house"[18] and avoided Stanford's drama department as she believed their productions were too "stuffy" and "safe".

[18][19] She had planned to enter Stanford's Ph.D. English program and eventually pursue a career as a writer or a journalist, but changed her mind after getting frustrated by the "deadly dry" honors courses.

[16][19] She subsequently applied to the Yale School of Drama, performing Bertolt Brecht's Saint Joan of the Stockyards at her audition, and was accepted.

Weaver performed in the first production of the Stephen Sondheim musical The Frogs while at Yale in 1974, alongside Larry Blyden and fellow students Meryl Streep and Durang.

[16] In 1974 she made her Broadway debut in the William Somerset Maugham play The Constant Wife acting opposite Ingrid Bergman.

Weaver appeared two years later as Warrant Officer / Lieutenant Ripley in Ridley Scott's blockbuster film Alien (1979), in a role initially designated to co-star British-born actress Veronica Cartwright until a late change in casting.

Cartwright stated to World Entertainment News Network (WENN) that she was in England ready to start work on Alien when she discovered that she would be playing the navigator Lambert in the project, and Weaver had been given the lead role of Ellen Ripley.

[33] Weaver appeared in an off-Broadway production of Durang's comedy Beyond Therapy in 1981, which was directed by then-fledgling director Jerry Zaks.

[34] She next appeared opposite Mel Gibson as British Embassy officer Jill Bryant in the Peter Weir directed romantic drama The Year of Living Dangerously (1982) which was released to critical acclaim.

Critic Roger Ebert wrote "Weaver, who is onscreen almost all the time, comes through with a very strong, sympathetic performance: She's the thread that holds everything together.

The same year, she appeared opposite Harrison Ford in a supporting role as main antagonist Katharine Parker in the comedy-drama Working Girl.

Weaver returned to the big screen with Alien 3 (1992) and Ridley Scott's 1492: Conquest of Paradise (1992) in which she played the role of Queen Isabella.

[45] In 1997, she appeared in Ang Lee's The Ice Storm as Janey Carver, a bored but stylish housewife trapped in a failed marriage.

[46][47] In 1999, she co-starred as Gwen DeMarco in the science fiction comedy Galaxy Quest[48] and as Alice Goodwin, a mother and school nurse whose negligence results in the accidental drowning of a friend's toddler in the drama A Map of the World, earning her a third nomination for the Golden Globe Award for Best Actress in a Motion Picture – Drama for the latter.

[49][50][51] In 2001, Weaver appeared in the comedy Heartbreakers playing the lead role of a con-artist alongside Jennifer Love Hewitt, Ray Liotta, Gene Hackman and Anne Bancroft.

In February 2002, she featured as a guest role in the Futurama episode "Love and Rocket", playing the female Planet Express Ship.

[69] Critic Brian Lowry of Variety praised its ensemble, specifically Weaver citing her as "representing an inspired choice to portray Elaine, someone brimming with integrity, pain and grit all at once.

[71] In 2013, Weaver returned to Broadway in the Christopher Durang play Vanya and Sonia and Masha and Spike (2013) alongside David Hyde Pierce, Kristine Nielsen, and Billy Magnussen at the John Golden Theatre.

[76][77] Weaver appeared in the film Exodus: Gods and Kings (2014) playing Tuya, directed by Ridley Scott, alongside Christian Bale, Joel Edgerton and Ben Kingsley.

[88][89] On September 23, 2019, Variety reported that Weaver and Kevin Kline are set to reunite again (after Dave and The Ice Storm) for The Good House, a drama from Steven Spielberg's Amblin Partners and Universal Pictures.

[102] Weaver will make her West End debut as Prospero in the revival of the William Shakespeare play The Tempest directed by Jamie Lloyd at the Theatre Royal, Drury Lane in 2025.

[106] In October 2006, Weaver gave a news conference at the start of a United Nations General Assembly policy deliberation where she outlined the threat to ocean habitats posed by deep-sea trawling, an industrial method for catching fish.

[107] On April 8, 2008, in the Rainbow Room, Weaver hosted the annual gala of the Trickle Up Program, a non-profit organization focusing on those (mainly women and disabled people) in extreme poverty.