Nicholas Stoller has written the script for "Captain Underpants", which centers on two fourth graders who are best friends and draw comics that they sell on the playground, the Hollywood Reporter said.
Their creation, "Captain Underpants", becomes real when the duo accidentally hypnotize the school's mean principal who turns into an actual superhero.
Scholastic first launched the book in September of 1997, and there are now more than 50 million Pilkey books in print in the US alone.
DreamWorks Animation's development executive Damon Ross is overseeing the project, which does not have a release date yet.
Letterman has previously directed "Shark Tale" and "Monsters vs Aliens" for the studio.
Letterman and Stoller worked together on 2010's "Gulliver's Travels", the Jack Black comedy fantasy that the former directed and the latter co-wrote.