Slowed by a costly fumble and two missed field goals in the first half, the fourth-ranked Seminoles used a 35-3 run in a 20-minute span of the second half Saturday night to remain unbeaten with a 49-37 over 10th-ranked Clemson.
"We just knew we had to keep scoring points to help our defense out," Manuel said. "Those guys [Clemson], they could throw up 50 points easily."
The biggest Atlantic Coast Conference game in years was a wild one for a while before Manuel put the Seminoles' offense into high gear to away.
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Seminoles (4-0, 2-0) emerged as national contenders for the first time in a long time, since Bobby Bowden was directing Florida State in the early 2000s, and Manuel will likely start showing up prominently on more than a few Heisman Trophy watch lists.
Clemson (3-1, 0-1) built a 28-14 lead early in the third quarter on a 52-yard pass from All-American receiver Sammy Watkins to Andre Ellington before the Seminole explosion.
"The game got away from us.... We have to stay focused," Clemson's Andre Ellington said.
The two teams combined for 1,093 yards offense as Clemson put up 426 yards against the nation's top-ranked defense.
Manuel was brilliant, completing 27 of 35 passes for a career-high 380 yards while rushing for another 102 to become the first Seminole quarterback since Charlie Ward in 1992 to pass for more than 300 yards and run for over 100 in a game.
"They were mixing up looks and bringing in blitzes from everywhere and he made plays when he had to," said Florida State coach Jimbo Fisher, in his third season as Bowden's successor. "I don't remember him making a bad decision all night."
Manuel got plenty of help from the tailback tandem of Chris Thompson and James Wilder Jr., who each scored twice and accounted for 168 more rushing yards with Thompson's 103 giving him 300 in two ACC games.
"We couldn't stop the run," Clemson coach Dabo Swinney said. "Right there at the end, the momentum change late in the third quarter going into the fourth quarter, we just weren't able to turn it back."
Florida State trailed until late in the third quarter, taking its first lead at 35-31 on Manuel's 29-yard touchdown pass to Rodney Smith. The Seminoles, who finished with 667 yards, built a 49-31 lead before Clemson scored late.
Florida State had another 211 yards in punt and kickoff returns, including a 90-yard kickoff return by Lamarcus Joyner that set up Manuel's touchdown throw to Rashad Greene that brought the Seminoles to within 31-28.
"That was two very good football teams throwing haymakers at each other right from the opening bell," Fisher said. "I can't say enough about our player's ability to overcome adversity."
Florida State, which just missed scoring 50 or more points for a fourth straight game, is averaging 56.2 points and 574.5 yards offense a game as it prepares to step out of conference play next weekend at South Florida.
The first half was eerily similar to last year's game at Clemson when the Tigers rolled up 443 yards and 26 first downs in a 35-30 win when Manuel was sidelined with a shoulder injury.
The two teams combined for 361 yards offense in a wild first quarter Saturday.
The Tigers needed just 86 seconds to reach the end zone as DeAndre Hopkins blew past Florida State safety Terrence Brooks on a 60-yard scoring bomb from Tajh Boyd - the first touchdown scored against the Seminole defense this season. But more were to come.
A trick play set up Clemson's second TD, a 6-yard run by Ellington. Darrell Smith got a yard on a shovel pass from holder Spencer Benton on a fake field goal from the Florida State 15 two plays earlier.
Yet another trick play gave Clemson its 28-14 lead when Watkins took a lateral from Boyd and then threw back across the field to Ellington on a 52-yard scoring play. Although Watkins had 109 all-purpose yards, he was kept out of the end zone.
But Florida State responded quickly, sandwiching a pair of TDs around a 50-yard field goal by Clemson's Chandler Catanzaro.
Clemson led 21-14 at the half, capitalizing on a fumble by Greene to score the go-ahead touchdown on a 17-yard pass from Boyd to Brandon Ford.
Boyd completed 20 of 36 passes for 237 yards and three touchdowns for Clemson.