"Big Nate" follows the adventures and misadventures of Nate Wright, a rebellious yet spirited sixth-grader, along with his fellow classmates and teachers. He is portrayed as a boy with little interest in studies or conforming to standards, which has led him into several conflicts with his social studies teacher Mrs. Godfrey, whom he considers to be his nemesis. Strips also focus on Nate's home life and friendships with his best friends Francis and Teddy. Answering questions from fans in the Washington Post, Peirce revealed the following about the creation of the strip:
"Big Nate started out as more of a 'domestic humor' strip than it is now. It was my intention to feature a lot of stories about Nate's single dad, and all the comic possibilities inherent in that. But before too long, I realized that the part of the strip that I enjoyed most was the school humor. I'd been a teacher myself, and schools can be very funny places."