Virginia Tech scored 12 consecutive second-half points to overcome a 20-10 deficit and was in position to produce an upset that would have badly damaged the Seminoles' hopes for an Atlantic Coast Conference championship.
Manuel, however, drove Florida State 71 yards in nine plays over the course of 99 seconds and hit Rashad Greene with the winning touchdown pass of 39 yards. Manuel then tacked on a 2-point conversion with a pass to Nick O'Leary.
The Seminoles won their fourth straight game, improved to 9-1 and climbed to 6-1 in the ACC's Atlantic Division. Clemson can also reach 6-1 in the division on Saturday in a meeting with Maryland, but the Tigers lost to Florida State earlier in the season.
That means a win for Florida State over Maryland next week will give the Seminoles the division crown and put them in the ACC title game against the Coastal Division winner on Dec. 1 in Charlotte.
Virginia Tech suffered its third straight defeat, falling to 4-6 for the year and to 2-3 in the Coastal Division.
Manuel helped Florida State build its lead with touchdown passes of 25 yards to Greene in the second quarter and 10 yards to Greg Dent in the third. Manuel went 25-of-42 for 326 yards.
Virginia Tech began its comeback with a 5-yard scoring run from Logan Thomas late in the third period, a safety with 6:59 remaining in the fourth and a go-ahead field goal of 21 yards by Cody Journell with 2:19 to play.
The game was marred by a scary injury suffered by Virginia Tech safety Michael Cole in the third period. He was taken off the field in an ambulance after being part of a violent collision.
Virginia Tech officials later said Cole, who had been restrained on a stretcher, had full movement in his extremities and had suffered a neck sprain.