Manuel hit Bert Reed and Rashad Greene with touchdown passes in the span of 1:36 to bring the Seminoles back from a 14-3 deficit to their seventh victory in eight games.
Florida State (9-4) came up with three interceptions, including one that set up the second of Manuel's touchdown throws and one in the end zone with 2:48 to play that ended Notre Dame's last realistic hope of victory.
Manuel drove Florida State 84 yards in a march that began late in the third quarter and ended on the first play of the final period with an 18-yard throw to Reed. A two-point conversion attempt failed, leaving the Seminoles still facing a 14-9 deficit.
Notre Dame then called on quarterback Andrew Hendrix to replace a struggling Tommy Rees and Hendrix, on 2nd-and-10 from his own 31, threw the ball directly into the hands of Florida State's Nigel Bradham.
That set up Manuel's second touchdown throw, a 15-yarder to Greene.
Another two-point conversion try failed, but the Seminoles added a 29-yard field goal by Dustin Hopkins with 8:08 to play. That score was set up by a Manuel pass of 42 yards to Greene, who made a spectacular, juggling catch along the sidelines that withstood a video replay.
Manuel completed 20-of-32 passes for 244 yards.
Notre Dame wound up 8-5, finishing its season with consecutive losses after winning four in a row.
Florida State gave the Atlantic Coast Conference a 2-1 record in this year's bowl season with that league having five games left to play.