Willems was born in the Chicago suburb of Des Plaines, Illinois and was raised in New Orleans, where he graduated from Trinity Episcopal School and the Isidore Newman School. He graduated cum laude from New York University's Tisch School of the Arts. He married Cheryl Camp in Brooklyn, New York, in 1997. Willems now resides with his family in Northampton, Massachusetts.
Willems first became interested in cartoon art when he was just a child. When he was 3 or 4 he started to draw and create his own characters. Willems enjoyed writing stories about his characters to share with others. However, he was disappointed when adults would praise his work out of politeness. To fix this dilemma Willems started writing funny stories. He knew that even polite adults could not fake a laugh. So when the adults laughed he knew his story was good and if the adults still gave polite comments then he knew his story was bad.
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 started 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 along with making a promo for Cartoon Network and animating the opening for a show on Nickelodeon. 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 Codename: 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), Knuffle Bunny: A Cautionary Tale (2005), and Knuffle Bunny Too: 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 books won the Theodor Seuss Geisel Medal in 2008 and 2009, and Geisel Honors in 2011, 2012, 2013, 2014 and 2015. In 2010, Willems introduced a new series of books featuring Cat the Cat, also aimed at early readers.
He made several appearances on NPR's All Things Considered as the show's "radio cartoonist" in 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.
Mo Willems currently resides in Massachusetts with his wife, Cher, and his daughter, Trixie. In 2003, Willems left his career in television and became a stay-at-home father for his daughter. In an interview with Sherry Joe Crosby from the Los Angeles Daily News, Willems shared that there were two reasons for making this decision. Willems explained the two reasons,
"One is selfish and the other is kind of selfish. The very selfish reason is if I wrote books I would be able to work at home. I have a young child and I love the idea of having lunch with my family every day. I wanted to be back in the business where I could work at home. The other kind of selfish reason is that I had more freedom in writing books than I had in writing for television."
In another interview with Samantha Critchell of the Springfield News he stated, "Trixie is funny. My books aren't quite as good as her jokes." One of Willems' characters in his famous story Knuffle Bunny, is named after his daughter Trixie. Willems is well known for being a family man.