The win gave the Tigers (10-0, 7-0 ACC) at least 10 victories for the fifth straight season and their first 10-0 start since they won their only national championship in 1981.
With 13 straight wins, the Tigers have their longest winning streak in 34 years.
Syracuse (3-7, 1-5 ACC) put up a good fight for embattled coach Scott Shafer but lost for the seventh time in a row. Syracuse is 1-10 all time against the No. 1 team.
Watson completed 34 of 47 passes for 360 yards, two touchdowns and one interception. He ran for 105 yards and a score.
Greg Huegel chipped in with three field goals for the Tigers.
Syracuse made a game of it from the start, repeatedly finding gaping holes in the Clemson defensive line. The Orange rushed for 242 yards and scored their three touchdowns on the ground against a team that had allowed only nine rushing scores.
The Orange refused to wilt when they fell behind, even with Zack Mahoney, a junior college transfer and walk-on making his second start at quarterback.
Leading 31-17 at halftime, Clemson failed to score in the third quarter for the first time this season and the Orange closed to 31-24 on Mahoney's 14-yard run.
The Orange defense held Wayne Gallman in check as he managed 66 yards on 15 carries, boosting his season total to 1,043. His 14-yard run on fourth-and-2 early in the fourth quarter, though, proved key against the fired-up Orange. It set up Huegel's 31-yard field goal with 13:33 to play for a 34-24 lead.
The Orange rallied again when George Morris ripped off a 51-yard run that set up a 24-yard field goal by Cole Murphy early in the fourth to make it a one-possession game, but that was as close as the Orange would get.
Mahoney, fifth on the depth chart in preseason, acquitted himself well in his debut in September, throwing for three TDs against then-No. 8 LSU in a 34-24 loss. He was just as good in this one despite some early jitters, finishing with 76 yards and two TDs rushing. He was 8 of 21 for 80 yards passing.
Shafer said "these guys can make plays in space" when asked about Clemson earlier in the week. He wasn't kidding. Rarely pressured, Watson was 20 of 26 for 266 yards and two touchdowns in the first half, spreading the ball to four receivers as the Tigers took the lead after losing two fumbles.
After Syracuse forged a surprising 14-all tie late in the first quarter, the Tigers struck twice in four minutes as Watson used the short passing game to put the Orange defense on its heels. He completed five passes for 53 yards as Clemson moved deep into Syracuse territory, then hit Peak in the left corner of the end zone to break the tie.
The last time the Tigers played in the Carrier Dome they were ranked No. 3 and dismantled the Orange 49-14 in Syracuse's Atlantic Coast Conference debut in 2013.
Clemson appeared poised for another rout, scoring twice in the first two minutes.
Watson hit Peake with a 64-yard pass on the Tigers' first play from scrimmage and Gallman scored from the 11 on the next play for a 7-0 lead after just 33 seconds.
Mahoney then fumbled the first play for the Orange, and Clemson defensive end Kevin Dodd recovered at the Syracuse 23. Watson's 3-yard run gave the Tigers a 14-0 lead after just 1:59 of play.
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