With their fourth straight win, the Seminoles (6-3, 4-2 Atlantic Coast Conference) qualified for a bowl game for an NCAA-best 30th consecutive year.
Boston College (2-7, 1-5), which had gone to a bowl game for 12 straight years, was guaranteed its first losing season since 1998 and was eliminated from bowl contention.
Manuel completed 12 of 16 passes for 180 yards and ran 16 times for 37 yards. Devonta Freeman ran for 62 yards and two touchdowns, and Nick O'Leary caught three passes for 87 yards.
Chase Rettig completed 11 of 18 passes with one touchdown and one interception for Boston College, splitting time with freshman Josh Bordner after the first six drives resulted in five punts and a fumble. Bordner was 1 of 2 for 37 yards, and he ran seven times for 45 yards.
Manuel did most of the damage in a dominant first half, when Florida State scored on three consecutive possessions to blow the game open. With 4:51 to play in the second quarter, the Seminoles led 28-0; they had outgained BC 214 yards to 16 and held the Eagles without a first down.
Bordner came into the game and, sharing time with Rettig on the drive, led BC 74 yards to the Florida State 1 before Rolandan Finch fumbled.
Finch, a former fourth-stringer who had 243 yards against Maryland last week, had two fumbles in the game while gaining 59 yards on 28 carries.
Luke Kuechly had 20 tackles — 12 solo — for Boston College, his 31st straight game with 10 or more.
Manuel threw for 321 yards and two touchdowns last week in a 34-0 victory over North Carolina State — the Seminoles' fourth consecutive game with more than 425 yards of total offense. Against BC they had 307.
Florida State failed to get a first down on its first possession, but it got the ball back on the BC 2 when Anthony McCloud knocked the ball free from Finch and Smith fell on it. Two plays and a penalty later, Manuel hit Bert Reed for an 8-yard touchdown pass.
The Seminoles scored early in the second quarter on Freeman's 12-yard run and, after another BC three-and-out, Manuel completed a 58-yard pass to O'Leary before taking it in himself from 1 yard out to make it 21-0. After another BC three-and-out, Freeman marched Florida State down the field before scoring from the 3 to give the Seminoles a 28-0 lead.
Bordner entered the game for BC and, on his first snap, ran 25 yards for the Eagles' first first down of the game. From the Seminoles' 39 he hit Bobby Swigert on a 37-yard completion that brought the ball to the 2.
But Finch was stuffed for a 1-yard gain on first-and-goal, and on second down he lost the ball on his way to the line of scrimmage.