In film, DeVito is known for his roles in One Flew Over the Cuckoo's Nest (1975), Terms of Endearment (1983), Head Office (1985), Ruthless People (1986), Twins (1988), Batman Returns (1992), Jack the Bear (1993), Junior (1994), 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). DeVito has voiced characters in numerous animated films including Space Jam (1996), Hercules (1997), The Lorax (2012), Smallfoot (2018), and Migration (2023). He both directed and starred in several films such as Throw Momma from the Train (1987), The War of the Roses (1989), Matilda (1996), and Death to Smoochy (2002). He has served as a producer on notable films such as Reality Bites (1994), Pulp Fiction (1994), Gattaca (1997), Erin Brockovich (2000), and Garden State (2004).
DeVito married actress Rhea Perlman in 1982; they have three children. The couple separated in 2012.