Willems was raised in New Orleans and attended the Isidore Newman School. He graduated cum laude from New York University's Tisch School of the Arts. He married Cheryl Lynn Camp in Brooklyn, New York, in 1997. Willems now resides with his family in Northampton, Massachusetts.

After graduating from Tisch, Willems spent a year traveling around the world drawing a cartoon every day, all of which have been published in the book You Can Never Find a Rickshaw When it Monsoons.

Returning to New York, he kicked off his career as a writer and animator for Sesame Street, where he earned six Emmy Awards for writing during his tenure from 1993 to January 2002. During this period he also performed stand-up comedy in NYC and recorded essays for BBC Radio. He later created two animated television series: The Off-Beats for Nickelodeon's Kablam, and Sheep in the Big City for Cartoon Network. Sheep in the Big City was a success with the critics but ultimately failed to attract sufficient viewership and was canceled after two seasons. Willems later worked as head writer on the first four seasons of Kids Next Door, created by one of his colleagues from Sheep, Tom Warburton. He left the show to pursue his writing career.

Since 2003, Willems has authored numerous books for young children, many of which have garnered significant critical acclaim. The New York Times Book Review referred to Willems as "the biggest new talent to emerge thus far in the 00's" ... and to his pigeon character as "one of this decade's contributions to the pantheon of great picture book characters."

Three of Willems' books have been awarded a Caldecott Honor: Don't Let the Pigeon Drive the Bus! (2004), A Cautionary Tale (2005), and A Case of Mistaken Identity (2008). Recently he has been creating the Elephant and Piggie books, an early reader series about a friendly elephant and pig. Elephant and Piggie won the Theodor Seuss Geisel Medal in 2008 and 2009, but the series has not been as universally well-received as Willems' earlier work. In 2010, Willems introduced a new series of books featuring Cat the Cat, also aimed at early readers.

He has made several appearances on NPR's All Things Considered as the show's "radio cartoonist" since 2008.

Willems' books have been translated into a number of languages, spawned animated shorts that have twice been awarded the Carnegie Medal (Knuffle Bunny, 2007, and Don't Let the Pigeon Drive the Bus, 2010), and been developed into theatrical musical productions. His illustrations, wire sculpture, and carved ceramics have been exhibited in galleries and museums across the nation.

Willems has worked on a number of books on his own, as well as submitting work for other compilations.

As author

• Pigeon series
• Don't Let the Pigeon Drive the Bus! ... Caldecott Honor 2004
• Don't Let the Pigeon Stay Up Late!
• The Pigeon Finds a Hot Dog!
• The Pigeon Has Feelings, Too!
• The Pigeon Loves Things That Go!
• The Pigeon Wants a Puppy
• A Cautionary Tale ... Caldecott Honor 2005
• A Case of Mistaken Identity ... Caldecott Honor 2008
• Knuffle Bunny Free: an Unexpected Diversion
• Edwina, the Dinosaur Who Didn't Know She Was Extinct
• Leonardo, the Terrible Monster
• Time to Pee!
• Time to Say "Please"! ... a book about manners (2005, Hyperion Books)
• You Can Never Find a Rickshaw When It Monsoons ... a compilation of cartoons Willems drew while taking a year-long backpacking trip around the world (2006, Hyperion Books)
• Elephant and Piggie series
• Today I Will Fly!
• My Friend is Sad
• There is Bird on Your Head!
• I Am Invited to a Party!
• I Will Surprise my Friend!
• I Love My New Toy!
• Are You Ready to Play Outside?
• Watch Me Throw the Ball!
• Pigs Make Me Sneeze!
• Elephants Cannot Dance!"
• I Am Going!
• Can I Play Too?
• Naked Mole Rat Gets Dressed
• Big Frog Can't Fit In: A pop-up book
• Cat the Cat series
• Cat the Cat, Who Is That?
• Let's Say Hi to Friends Who Fly
• What's Your Sound, Hound the Hound?
• Time to Sleep, Sheep the Sheep!

As contributor

• Why Did the Chicken Cross the Road?
• Thanks and Giving All Year Long
• Everyman for Himself
• Bizarro World
• Reckless
• Guys Write for Guys Read
• 9/11 Comic Book Collaboration