Andre Ellington added a pair of rushing touchdowns for the Tigers (3-0).
Watkins scored in the first quarter after taking an inside handoff from Boyd and rushing past the right side of Furman's defense. The All-American sophomore receiver spent the past two games on the sideline, suspended for a May drug arrest. He finished with four catches for 52 yards.
Boyd's three scoring throws gave him 43 for his career, second all-time at Clemson and just six behind the record held by Charlie Whitehurst.
Furman of the Football Championship Subdivision opened 0-3 for the first time since 1979.
Clemson coach Dabo Swinney joked this week the Tigers had gained more than 500 yards of offense in both victories without Watkins and his star better not mess it up.
Clemson finished with 498 yards against Furman.
It didn't take long, though, for Watkins to make his mark. He had catches of 12 and 19 yards on Clemson's first scoring drive, which ended on Ellington's 10-yard run.
Watkins was dazzling the next time the Tigers had the ball, running along the offensive line to take an inside handoff from Boyd. Watkins turned it up the right side and outran two Furman defenders to the end zone for his first score of the season.
The Tigers' offense, though, had to work a bit harder with Watkins back for their instate rival — Furman's a 35-mile drive northeast of Clemson — than when Watkins missed last week's 52-27 victory over Ball State. In that one, Clemson scored touchdowns on five of its first six possessions and was up 45-10 at half.
This time, Boyd and the first-teammers needed a third-quarter surge — and some help from the defense — to put the game away.
Linebacker Quandon Christian's interception deep in Furman territory led to Ellington's second touchdown. Boyd was back at it a series later, finding a wide-open Brandon Ford on a 30-yard scoring pass and a 34-7 lead.
Boyd's final touchdown came when he hit Martavis Bryant in triple coverage on a 39-yard pass.
A day that started with excitement over Watkins' return, ended with plenty of questions about Clemson's defense with No. 5 Florida State ahead next Saturday night.
There were many fans dress in Watkins' No. 2 Clemson jersey during pre-game tailgates and Watkins got a rousing ovation when he stepped off the bus for the traditional Tiger walk entrance into the locker room.
Watkins' touchdown was the first time he'd rushed for a score at Clemson.
The Tigers bogged down after that, ending two second-quarter drives with Chandler Catanzaro field goals of 46 and 22 yards. Catanzaro had made 14 consecutive kicks, tying Obed Ariri's school mark.
What was troubling, though, for a team that's yet to live down a 70-33 Orange Bowl embarrassment to West Virginia was Furman's success moving the ball on the defending ACC champions.
Paladins quarterback Reese Hannon drove 63 yards to the Clemson 5 on the opening series. Furman coach Bruce Fowler switched from a fourth down field goal attempt into a trick pass, but Will King overthrew fullback Tony Caldwell in the end zone and Rashard Hall intercepted to end the threat.
Furman lost another scoring chance with a bad snap on Ray Early's 42-yard field goal attempt as Clemson smothered the ball.
The Paladins finally broke through with Hannon's 37-yard touchdown pass to Jason Snellings to cut the lead to 17-7. Jerodis Williams also had a 39-yard run right before to set up the scoring play.
Hannon was 19 of 29 for 235 yards in his first collegiate start. Furman finished with 352 yards.