In 1979, he was given a role in Michael's Cimino's Heaven's Gate, from which he was fired. Since then, he has collaborated with directors who represent a virtual encyclopedia of modern cinema: James Wan, Robert Eggers, Sean Baker, Kenneth Branagh, Kathryn Bigelow, Sam Raimi, Alan Parker, Walter Hill, Mary Harron, Wim Wenders, Anton Corbijn, Zhang Yimou, Wes Anderson, Martin Scorsese, David Lynch, Oliver Stone, William Friedkin, Werner Herzog, Lars Von Trier, Abel Ferrara, Spike Lee, and David Cronenberg, among other.

Dafoe has been recognized with four Academy Award nominations: Best Actor in a Supporting Role for Platoon, Best Actor in a Supporting Role for Shadow Of The Vampire, for which he also received Golden Globe and Screen Actors Guild nominations, Best Actor in a Supporting Role for The Florida Project, for which he also received Golden Globe and Screen Actors Guild nominations, and most recently, Best Leading Actor for At Eternity's Gate, for which he also received a Golden Globe nomination. Among his other nominations and awards, he has received two Los Angeles Film Critics Awards, a New York Film Critics Circle Award, a National Board of Review Award, two Independent Spirit Awards, Venice Film Festival Volpi Cup, as well as a Berlinale Honorary Golden Bear for Lifetime Achievement.

Willem was born in Appleton, Wisconsin, to Muriel Isabel (Sprissler), a nurse, and William Alfred Dafoe, a surgeon. He is of mostly German, Irish, Scottish, and English descent. He and his wife, director Giada Colagrande, have made three films together: Padre, A Woman, and Before It Had A Name.

Dafoe is one of the founding members of The Wooster Group, the New York based experimental theatre collective. He created and performed in all of the group's work from 1977 thru 2005, both in the U.S. and internationally. Since then, he worked with Richard Foreman in Idiot Savant at The Public Theatre (NYC), with Robert Wilson on two international productions: The Life & Death of Marina Abramovic and The Old Woman opposite Mikhail Baryshnikov and developed a new theatre piece, directed by Romeo Castellucci, based on Nathaniel Hawthorne's The Minister's Black Veil. He recently completed work on Marina Abramovic's opera 7 Deaths of Maria Callas.