The Biletnikoff Award winner made the long-expected announcement Friday night with a message posted on his Twitter account.
Lee was the nation's top receiver as a sophomore in 2012, catching a school-record 118 passes for 1,721 yards and 14 touchdowns.
He struggled with injuries throughout his junior year, finishing with just 57 receptions for 791 yards and four TDs.
New USC coach Steve Sarkisian already has lost four key underclassmen to the NFL draft in the last three weeks since the Trojans' victory in the Las Vegas Bowl.
Lee joins safety Dion Bailey, defensive lineman George Uko and center Marcus Martin in the draft.