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Keaton gained early recognition for his comedic roles in Night Shift (1982), Mr. Mom (1983), and Beetlejuice (1988). He gained wider stardom portraying the title superhero in Batman (1989) and Batman Returns (1992). He took roles in Clean and Sober (1988), Much Ado About Nothing (1993), The Paper (1994), Multiplicity (1996), Jackie Brown (1997), Jack Frost (1998), Herbie: Fully Loaded (2005), and The Other Guys (2010). He also performed voice roles in the animated films Cars (2006), Toy Story 3 (2010), and Minions (2015).

Keaton experienced a career resurgence after taking a starring role as a faded actor attempting a comeback in Alejandro González Iñárritu's Birdman (2014), for which he won a Golden Globe Award for Best Actor and a nomination for the Academy Award for Best Actor. He has since acted in biographical dramas such as Spotlight (2015), The Founder (2016), The Trial of the Chicago 7 (2020), and Worth (2021). He portrayed the Vulture in Spider-Man: Homecoming (2017), while also reprising his roles as Man in The Flash (2023) and the title role in Beetlejuice Beetlejuice (2024).

Keaton starred as a journalist in the HBO film Live from Baghdad (2002). He portrayed a drug-addicted doctor in the Hulu limited series Dopesick (2021), for which he won a Primetime Emmy Award and Golden Globe Award for Best Actor. Keaton directed the films The Merry Gentleman (2008) and Knox Goes Away (2023), in which he also played the starring role.