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DeVito is known for his film roles in One Flew Over the Cuckoo's Nest (1975), Terms of Endearment (1983), Romancing the Stone (1984), The Jewel of the Nile (1985), Ruthless People (1986), Throw Momma from the Train (1987), Twins (1988), The War of the Roses (1989), Batman Returns (1992), Jack the Bear (1993), Junior (1994), Matilda (1996), L.A. Confidential (1997), The Big Kahuna (1999), Big Fish (2003), Deck the Halls (2006), When in Rome (2010), Wiener-Dog (2016), and Jumanji: The Next Level (2019). He has voiced roles in such films as Disney's Hercules (1997), The Lorax (2012), Smallfoot (2018), and Migration (2023).

In 1991, DeVito and Michael Shamberg founded production company Jersey Films. Soon afterwards, Stacey Sher became an equal partner. The production company is known for films such as Pulp Fiction (1994), Garden State (2004) and Freedom Writers (2007). He would later create a second production company, Jersey Films 2nd Avenue, with his daughter, Lucy, and son, Jake. DeVito also owned Jersey Television, which produced the Comedy Central series Reno 911!. DeVito and his wife Rhea Perlman starred together in his 1996 film Matilda, based on Roald Dahl's children's novel. DeVito was also one of the producers nominated for an Academy Award for Best Picture for Erin Brockovich (2000).

From 2012 to 2013, DeVito played Willie Clark in the West End revival of Neil Simon's The Sunshine Boys. He made his Broadway debut as Gregory Solomon in the revival of Arthur Miller's The Price (2017), earning a Tony Award nomination for his performance. He returned to Broadway in the Theresa Rebeck play I Need That (2023).