She made her feature film debut with a starring role in Purple People Eater (1988), for which she won a Young Artist Award for "Best Actress Under Nine Years of Age".

Birch rose to prominence as a child star during the 1990s through a string of parts in films, including Paradise (1991), Patriot Games (1992), Hocus Pocus (1993), Monkey Trouble (1994), Now and Then (1995), and Alaska (1996).

[20] At age 11, Birch starred in the Halloween-set fantasy film Hocus Pocus (1993), playing Dani Dennison, the younger sister of a teenage boy who inadvertently resurrects a trio of witches.

Writing for Variety, David Kronke called it "a thoughtful and sensitive examination of how a family copes with grief", and said of the performances, "De Mornay … digs deep and comes up with a character that seems true; Burstyn and Birch competently complement [her]".

Birch's portrayal of insecure teenager Jane Burnham in American Beauty, Sam Mendes' dark dramedy about the struggles of a middle class household, was roundly praised by critics,[31][32] with Peter Travers of Rolling Stone writing that she "[glimmered] with grown-up radiance".

[33] The performance earned her a BAFTA nomination for Best Supporting Actress,[34] while the film was the recipient of the 1999 Academy Award for Best Picture and grossed over US$356 million worldwide,[35][36] emerging as the biggest commercial success of Birch's career to date.

In a mixed review for Variety, Derek Elley stated that Birch gave "an effectively creepy lead [performance]", but called the film "clunky" in its "attempt to merge the psychothriller and teen movie genres".

[42][43][2] James Berardinelli found Birch's part to be her "first effectively developed role" since American Beauty, commending the actress for the "quirkiness [and the] underlying sense of melancholy and ennui" in her portrayal of Enid Coleslaw.

[44] Meanwhile, A. O. Scott said in his appraisal for The New York Times: Thora Birch, whose performance as Lester Burnham's alienated daughter was the best thing about American Beauty, plays a similar character here, with even more intelligence and restraint.

Enid's capacity for scorn is unlimited: her plucked eyebrows might illustrate a dictionary entry for "supercilious," and her quiet voice shoots darts of sarcasm in every direction.

The independent feature received mixed reviews, but Empire's Angie Errigo thought Birch's portrayal of whistleblower Karen Cross was "terrific".

In Dark Corners (2006), a psychological horror-thriller about a young woman who wakes up one day as a different person, Birch starred in the dual role of Susan Hamilton and Karen Clarke.

[53] Next, she took on the role of journalist Sidney Bloom in The Pregnancy Pact, a Lifetime movie based on the true story of a group of high schoolers in Gloucester, Massachusetts, who plotted to get pregnant at the same time and raise their children communally.

[55] Later that year, Birch was cast—in what would have been her stage debut—as Lucy in the off-Broadway revival of Hamilton Deane's Dracula,[56] but was subsequently dismissed from the production for the alleged behavior of her father—her manager at the time—who was reported to have physically threatened one of the show's cast members during a rehearsal.

[60][61] After devoting herself to academic pursuits, which included securing a degree in legal studies through Kaplan University,[62] Birch returned to acting in 2015 with a recurring role as software engineer Morgan on the first season of USA Network's Colony.

[64] Birch starred as a left-wing activist in the 2018 political thriller Affairs of State, which Noel Murray of The Los Angeles Times called "refreshingly smart".

[65] In a less favorable review for Forbes, Luke Y. Thompson wrote, "[cinematographer] Horacio Marquinez gamely films everything like it's an art movie, though there's one scene in which he shoots Birch so unflatteringly that you wonder what she must have done to make him mad".

[68][69] The following year, she played a supporting role in the crime thriller Above Suspicion, which—after Patriot Games and Clear and Present Danger in the 1990s—marked her third collaboration with director Phillip Noyce.

Between 2019–2020, Birch appeared in the role of Mary (aka "Gamma") on the tenth season of AMC's post-apocalyptic horror series The Walking Dead,[72] with Collider commenting that she brought "emotional depth" to the part.

Birch said she had been wanting to direct since she was "nine or ten years old" and that it was the subject matter which drew her to the project: "There's an element of abusive relationships in this story that I think so many of us can relate to … [it] captured the entire nation's attention in the middle of Covid … Everyone stopped and took a minute and [said] "Where’s Gabby?

Birch said it was the idea of "a return to the old radio dramas … from the [1920s and '30s]", as well as the luxury of acting with her voice and not having to endure "the harsh physical positions that the character is in", which drew her to the project.