The book was quickly made into a famed, 1940 Hollywood movie of the same name directed by John Ford and starring Henry Fonda as Tom Joad. The first part of the film version follows the book fairly accurately. However, the second half and the ending in particular are significantly different from the book. John Springer, author of The Fondas (Citadel, 1973), said of Henry Fonda and his role in film version of The Grapes of Wrath: "The Great American Novel made one of the few enduring Great American Motion Pictures."
The 2009 documentary American: The Bill Hicks Story revealed that The Grapes of Wrath was the favorite novel of the comedian Bill Hicks. He based his famous last words on Tom Joad's final speech: "I left in love, in laughter, and in truth, and wherever truth, love and laughter abide, I am there in spirit."
In July 2013 Steven Spielberg announced his plans to direct a remake of The Grapes of Wrath for DreamWorks.
Woody Guthrie's two-part song—"Tom Joad - Parts 1 & 2"—from the album Dust Bowl Ballads (1940), explores the protagonist's life after being paroled from prison. In 1988, Andy Irvine recorded both parts as a single song—"Tom Joad"—on Patrick Street's second album, No. 2 Patrick Street.
American rock singer-songwriter Bruce Springsteen named his eleventh studio album, The Ghost of Tom Joad (1995), after the character. The first track on the album is also called "The Ghost of Tom Joad". The song – and to a lesser extent, the other songs on the album – draws comparisons between the Dust Bowl and modern times.
The song "Dust Bowl Dance" by Mumford & Sons is based on the novel.
Bad Religion have a song entitled "Grains of Wraith" on their 2007 album, New Maps of Hell. Bad Religion lead vocalist, Greg Graffin is a fan of Steinbeck's.
The progressive rock band Camel released in 1991 an album titled Dust and Dreams inspired on the novel.
An opera based on the novel was co-produced by the Minnesota Opera and Utah Symphony and Opera, with music by Ricky Ian Gordon and libretto by Michael Korie. The world premiere performance of the opera was given in February 2007, to favorable local reviews.
The Steppenwolf Theatre Company produced a stage version of the book, adapted by Frank Galati. Gary Sinise played Tom Joad for its entire run of 188 performances on Broadway in 1990. One of these performances was filmed and shown on PBS the following year.
In 1990, the Illegitimate Players theater company in Chicago produced Of Grapes and Nuts, an original, satirical mash-up of The Grapes of Wrath and Steinbeck's acclaimed novella Of Mice and Men.