Boyd threw for a school-record 428 yards with five touchdown passes and Watkins added a school-record 202 yards receiving as the Tigers (No. 18 BCS, No. 14 AP) routed Wake Forest 42-13 on Thursday night.
Boyd was 27 of 38 and connected with Watkins for three plays of 50 or more yards, including a 61-yarder for a score.
"Tajh was just lights out," coach Dabo Swinney said. "And now maybe everybody will quit asking me about Sammy Watkins."
Watkins, who missed three games because of suspension and illness, had eight receptions. Boyd added touchdown throws of 9 yards to Brandon Ford, 12 yards each to Sam Cooper and DeAndre Hopkins and 2 yards to Charone Peake.
The Tigers (7-1, 4-1 Atlantic Coast Conference) scored the first 35 points, including a four-touchdown second quarter, in their fourth consecutive victory and fourth straight in the series with the Demon Deacons (4-4, 2-4).
Five days after Virginia Tech held Clemson to season lows in every significant offensive statistic except the final score, the Tigers rolled up 534 total yards and essentially ended this one at halftime.
"We expect to execute in a manner that we score every time we get the ball," Boyd said. "So when you don't do it, sometimes it's kind of frustrating. Sometimes it's kind of disappointing. But all you can do is just keep working, keep pushing."
Boyd broke Charlie Whitehurst's 10-year-old record of 420 yards passing after Watkins took care of the school's receiving mark of 197 yards set last month by Hopkins against Boston College.
"We knew that was coming," offensive coordinator Chad Morris said of Watkins. "You see that spark, and it just gives everybody that much energy. ... Getting him going at the right time -- this team's going to need him the most at this point in time in the season."
Morris said the coaches left Boyd in well into the fourth quarter because they wanted him to reach 400 yards passing for the first time -- and wound up with the record when he hit Martavis Bryant for 37 yards.
The Demon Deacons had minus-23 yards rushing in the first half. They've played two Top 25 teams and have been outscored 94-13 while allowing 1,146 total yards.
"I don't know that we didn't respect (Clemson's speed)," Wake Forest coach Jim Grobe said. "I think we didn't realize how fast those guys were."
D.J. Howard added a late 1-yard touchdown run for Clemson, which was legitimately concerned after its lackluster 38-17 victory over the Hokies. In that game, the Tigers managed just 160 yards passing, 135 yards rushing and 295 total yards -- a performance that left Morris vowing it wouldn't happen again.
It certainly didn't -- at least not during an overwhelming first half.
The defending ACC champions eclipsed last week's yardage total by halftime, gaining 343 yards before the break.
Watkins, who sat out for the Tigers' first three plays because he was three minutes late for a team meeting, got the offense rolling on its third possession. He slipped behind the Wake Forest secondary and Boyd found him down the left sideline for the 57-yard pass that set up his touchdown pass to Ford.
Watkins then made it 14-0 on the first play of the second quarter when he took a throw from Boyd near the sideline, shook off two tacklers and outran two more on his way to his first touchdown reception of the season.
"You give up a big play or two, that kind of gets everybody a little bit spooky back there and then you give up a couple more by not playing real aggressively," Grobe said.
Boyd, who also threw for five TDs last year in a home win against North Carolina, then hit Cooper with a scoring pass 6 minutes later, and by then, the Tigers were well on their way to their sixth win in seven meetings with Wake Forest.
Scenes from Saquon Barkley's Penn State homecoming
Former Penn State football legend Saquon Barkley returned to Happy Valley for their "White out" game -- and he was very busy.
Kansas State uses rushing attack to beat Nevada 38-17
— Will Howard pushed into the end zone on a 1-yard touchdown run to cap a 21-point fourth quarter, which sealed a 38-17 victory for Kansas State over Nevada on Saturday.
Will Howard wraps up Kansas State's win with another TD
Will Howard crosses goal-line for 1-yard rushing touchdown
Oklahoma's Lincoln Riley, angling for field position vs. Nebraska, 'might have been the first coach in history' to challenge his own team's INT
Referring to Oklahoma CB D.J. Graham's one-handed interception on fourth down at the Sooner 3-yard line in Saturday's win over Nebraska, Lincoln Riley said he "might have been the first coach in history to challenge a play we got an interception on."
College football today: Week 3 updates, highlights, biggest moments and more
Here are the best moments on and off the field from college football's Week 3.
Jarret Doege, West Virginia Mountaineers notch upset in front of sellout crowd, hold off No. 15 Virginia Tech Hokies
Jarret Doege threw two touchdown passes in front of a sold-out crowd, and West Virginia survived No. 15 Virginia Tech's furious rally en route to a 27-21 victory on Saturday.