As a film actress, Linney debuted with a minor role in Lorenzo's Oil (1992) and went on to receive Academy Award nominations for the dramas You Can Count on Me (2000), Kinsey (2004), and The Savages (2007).

She is also known for her performances in Congo (1995), Primal Fear (1996), The Truman Show (1998), Mystic River and Love Actually (both 2003), The Squid and the Whale (2005), The Nanny Diaries (2007), Hyde Park on Hudson (2012), Mr. Holmes (2015), Sully and Nocturnal Animals (both 2016).

Her mother, Miriam Anderson "Ann" Perse (née Leggett), was a nurse at the Memorial Sloan Kettering Cancer Center, and her father, Romulus Zachariah Linney IV, was a playwright and professor.

Linney spent summers with her father in New Hampshire and fell in love with the stage, working with the local theatre group beginning at the age of eleven.

From a naive, idealistic artist's groupie with a streak of crazy determination, her Nina emerges as a woman who is a lot stronger and more complicated than the terminally wounded bird-woman that is the character's traditional interpretation.

"[11] Linney first appeared in minor roles in a few early 1990s films, including Lorenzo's Oil (1992), Searching for Bobby Fischer (1993), and Dave (1993).

Throughout the 1990s, Linney appeared on stage on Broadway and elsewhere including in Hedda Gabler, for which she won the 1994 Joe A. Callaway Award,[12] and a revival of Holiday in December 1995 through January 1996 (the Philip Barry play upon which the 1938 movie starring Cary Grant and Katharine Hepburn was based).

She made her Hollywood breakthrough in 1998, praised for playing Jim Carrey's on-screen wife Meryl Burbank in Peter Weir's science-fiction comedy drama film The Truman Show.

In 2002, she starred in Wild Iris alongside Gena Rowlands and won her first Emmy Award[15] for Outstanding Lead Actress in a Miniseries or a Movie.

[16][17] Also in 2002, Linney appeared on Sandra Boynton's children's CD Philadelphia Chickens alongside Meryl Streep, Kevin Kline and Patti LuPone.

[18] In 2003, Linney appeared in Clint Eastwood's Mystic River alongside Sean Penn, Tim Robbins and Marcia Gay Harden.

[19] Linney received a BAFTA Award nomination for her performance as Annabeth Markum, the devoted second wife to Sean Penn's grief-stricken and revengeful character.

[20] That same year she also starred in the holiday film Love Actually alongside Hugh Grant, Emma Thompson, Alan Rickman, Colin Firth, and Liam Neeson.

[25] Linney appeared in the political satire Man of the Year (2006) alongside Robin Williams and the comedy-drama The Nanny Diaries opposite Scarlett Johansson and Chris Evans, based on the book by Emma McLaughlin and Nicola Kraus.

[30] In 2009, Linney took part of the We Are One: The Obama Inaugural Celebration at the Lincoln Memorial in which she read passages from Franklin D. Roosevelt, and John F. Kennedy.

According to the Presidential Inaugural Committee, "The Sunday afternoon performance will be grounded in history and brought to life with entertainment that relates to the themes that shaped Barack Obama, and which will be the hallmarks of his administration."

[32] That same year, Linney returned to television in Showtime's half-hour series about cancer, The Big C. She served as both an actress and executive producer on the show.

She starred as a suburban wife and mother who explores the emotional ups and downs of suffering cancer, and the changes it brings to her life and her sense of who she is.

The film received rave reviews, earning an 89% on Rotten Tomatoes with the consensus reading, "Mr. Holmes focuses on the man behind the mysteries, and while it may lack Baker Street thrills, it more than compensates with tenderly wrought, well-acted drama.

She appeared briefly in Tom Ford's critical hit Nocturnal Animals alongside Amy Adams, Jake Gyllenhaal, and Michael Shannon.

The consensus from the review aggregator Rotten Tomatoes is, "Well-acted and lovely to look at, Nocturnal Animals further underscores writer-director Tom Ford's distinctive visual and narrative skill".

[39] In 2018, Linney starred in a monologue play adapted from the Elizabeth Strout novel by Rona Munro titled My Name Is Lucy Barton, at the Bridge Theatre in London directed by Richard Eyre.

Its plot was described as a "joyful and hilarious" journey of a group of riotous working-class women from Dublin, whose pilgrimage to Lourdes in France leads them to discover each other's friendship and their own personal miracles."

[50] In 2022, Linney made her television directorial debut with the eleventh episode of Ozark's final season ("Pound of Flesh and Still Kickin'").