She gained emancipation from her parents at age fifteen, and soon achieved recognition for her leading role as Jen Lindley in the teen drama television series Dawson's Creek (1998–2003).

Williams received critical acclaim for playing emotionally troubled women coping with loss or loneliness in the independent dramas Wendy and Lucy (2008), Blue Valentine (2010), and Manchester by the Sea (2016).

[8] In 1997, unhappy with the roles she was being offered, Williams collaborated with two other actors to write a script titled Blink, about prostitutes living in a Nevada brothel, which despite being sold to a production company was never made.

[31][32][33] In 1998, Williams began starring in the teen drama television series Dawson's Creek, created by Kevin Williamson and co-starring James Van Der Beek, Katie Holmes, and Joshua Jackson.

[34] Reviewing the first season for The New York Times, Caryn James called it a soap opera that was "redeemed by intelligence and sharp writing" but found Williams to be "too earnest to suit this otherwise shrewdly tongue-in-cheek cast".

[54][55] On stage, Williams played Varya in a 2004 production of Anton Chekhov's drama The Cherry Orchard, alongside Linda Emond and Jessica Chastain, at the Williamstown Theatre Festival.

[56] The theater critic Ben Brantley credited her for "cannily play[ing] her natural vibrancy against the anxiety that has worn the young Varya into a permanent high-strung sullenness.

[60] The actor next appeared in Imaginary Heroes, a drama about a family coping with their son's suicide, and played an impressionable young woman fixated on mental health in the period film A Hole in One.

[65][66] Her film breakthrough came later in 2005 when Williams appeared in Ang Lee's drama Brokeback Mountain, about the romance between two men, Ennis and Jack (played by Heath Ledger and Jake Gyllenhaal, respectively).

[22] Deeming her the standout among the cast, Ed Gonzalez of Slant Magazine commended Williams for "fascinatingly spiking [Alma's] unspoken resentment for her sham of a marriage with a hint of compassion for Ennis's secret suffering".

The screenwriter Charlie Kaufman was impressed with her comic timing in Dick and thus cast her in his directorial debut Synecdoche, New York, an ensemble experimental drama headlined by Philip Seymour Hoffman.

[77][78][79] Two days after finishing work on Synecdoche, New York, Williams began filming Kelly Reichardt's Wendy and Lucy, playing the part of a poor and lonesome young woman traveling with her dog and looking for employment.

[80][82] Sam Adams of the Los Angeles Times considered her performance to be "remarkable not only for its depth but for its stillness" and Mick LaSalle commended her for effectively conveying a "lived-in sense of always having been close to the economic brink".

[93] The New York Times's reviewer A. O. Scott found Williams to be "heartbreakingly precise in every scene" and commended the duo for being "exemplars of New Method sincerity, able to be fully and achingly present every moment on screen together".

Initially skeptical about playing Monroe, as she had little in common with her looks or personality, Williams spent six months researching her by reading biographies, diaries and notes, and studying her posture, gait, and mannerisms.

Though the actor considered it to be a light-hearted film, Jenny McCartney of The Daily Telegraph found a darker undertone to it and favorably compared its theme to that of Blue Valentine.

[116] Jointly directed by Sam Mendes and Rob Marshall, it tells the story of a free-spirited cabaret performer (Williams) in 1930s Berlin during the rise of the Nazi Party.

[117] Her performance received mixed reviews;[118] Jesse Green of Vulture praised her singing and commitment to the role, but Newsday's Linda Winer thought her portrayal lacked depth.

Set entirely in the lunchroom of an office, it focuses on a young woman (Williams), who confronts a much older man (played by Jeff Daniels) for having sexual relations with her when she was twelve years old.

[5] Kenneth Lonergan's Manchester by the Sea starred Casey Affleck as Lee, a depressed man who separates from his wife, Randi (Williams), following the tragic death of their children.

[121][126] Several critics hailed Williams's climactic monologue, in which Randi confronts Lee, as the film's highlight; Justin Chang termed it an "astonishing scene that rises from the movie like a small aria of heartbreak.

[136][137] The critic David Edelstein bemoaned that Williams's work had been overshadowed by the controversy and went on to commend her "marvelous performance", noting how she conveyed her character's grief through "the tension in her body and intensity of her voice".

[141][145] Influenced by the MeToo movement, she provided off-screen inputs regarding her character's wardrobe and dialogue, but the critic Peter Bradshaw found it to be "an outrageously boring and submissive role".

[149] Fosse/Verdon, an FX miniseries about the troubled personal and professional relationship between Bob Fosse and Gwen Verdon, marked her first leading role on television since Dawson's Creek.

[141] John Doyle of The Globe and Mail lauded Williams for "play[ing] Verdon with a wonderfully controlled sense of the woman's total commitment to her art and craft while always standing on the edge of an emotional abyss.

[167][164] The film received critical acclaim;[168] Pete Hammond of Deadline Hollywood labeled Williams "gut-wrenchingly great" and Kyle Buchanan of The New York Times wrote that she "really goes for it, attacking this part like someone who knows she’s been handed her signature role".

[172] Describing Williams's off-screen persona, Debbie McQuoid of Stylist magazine wrote in 2016 that she is "predictably petite but her poise and posture make her seem larger than life".

[58]Erica Wagner of Harper's Bazaar has praised Williams for combining "startlingly emotional performance with a sense of groundedness" and the critic David Thomson opines that she "can play anyone, without undue glamour or starriness".

[175][184] Adam Green of Vogue considers Williams's ability to reveal "the inner lives of her characters in unguarded moments" to be her trademark, and credits her for not "trading on her sex appeal" despite her willingness to perform nude scenes.

[191] According to the review aggregator site Rotten Tomatoes and the box-office site Box Office Mojo, Williams's most critically acclaimed and commercially successful films are The Station Agent (2003), Brokeback Mountain (2005), Wendy and Lucy (2008), Blue Valentine (2010), Shutter Island (2010), Meek's Cutoff (2010), My Week with Marilyn (2011), Oz the Great and Powerful (2013), Manchester by the Sea (2016), Certain Women (2016), The Greatest Showman (2017), Venom (2018), Venom: Let There Be Carnage (2021), and The Fabelmans (2022).