Derrick Henry attended Yulee High School in Yulee, Florida, where he was a three-sport star in football, basketball, and track. He played as a running back for Yulee Hornets and set numerous records, including the national high school football record for career rushing yards, finishing with 12,124 yards and 153 career touchdowns. His senior year was especially remarkable, with a state-record 4,261 rushing yards and 55 touchdowns, including a single-game performance of 510 rushing yards, which was a Florida state record at the time. He was a dominant player throughout his four years at Yulee High School, never rushing for fewer than 100 yards in a game and averaging more than 250 yards a game across his high school career.