Cornerbacks Martin Jenkins and Darius Robinson each had pick-6 scores to help the Tigers to a 38-7 lead by halftime.
Backup Cole Stoudt had three touchdown passes, two to reserve Germone Hopper, in the blowout.
Boyd finished 14-of-23 passing for 169 yards. He was sacked twice.
Clemson opened 2-0 for a fourth straight season, also a program first. The Tigers are off next week and don't return to the field until opening the Atlantic Coast Conference season Sept. 19 at North Carolina State.
The only way this game might affect the Tigers after last week's stirring victory over Georgia was if they had lost to South Carolina State. While Boyd wasn't the crisp, Heisman chaser he was a week ago, he steadily led the Tigers in front and let the defense do the rest.
He directed a 13-play drive on Clemson's first series that ended with Chandler Catanzaro's 38-yard field goal. Two series later, Boyd had passes of 13 yards to Sammy Watkins, 18 yards to Charone Peake and 21 yards to Adam Humphries to set up the quarterback's 1-yard scoring leap for a 10-0 lead.
Jenkins, out all last season due to injury, increased the lead moments later after defensive lineman DJ Reader hit South Carolina State quarterback Richard Cue as he threw and the ball floated for an easy interception. Jenkins turned it up and cut the middle of the field for the score.
Robinson's interception came at the start of the second quarter, a 35-yard run to the end zone that made it 24-0.
South Carolina State finally broke its scoreless streak at Clemson the Bulldogs lost 54-0 in their only other game here in 2008 with Cue's 63-yard scoring pass to Tyler McDonald. McDonald added a 51-yard TD pass from TeDarrius Wiley in the fourth quarter. McDonald had a 74-yard touchdown catch in South Carolina State's opening loss to Coastal Carolina.
The scariest moment came when Boyd was slow getting up after a hit midway through the second quarter and jogged slowly to the sidelines. The official word was he lost his breathe and later returned to the game to direct a 77-yard TD drive that ended with D.J. Howard's 19-yard run.
Boyd didn't play in the second half, wearing a ball cap and counseling his backups. Clemson's reserves, though, kept the offense churning. Stoudt, the son of ex-NFL quarterback Cliff Stoudt, finished 19 of 20 for 143 yards, the best single-game showing percentage-wise in school history. The Tigers used four quarterbacks and had 14 players catch passes in the blowout victory.