The Bulls (6-1, 1-1 Big East) seemed to be back on track after a disappointing loss to Pittsburgh on Oct. 2, which knocked them out of the top 10 in the polls.
Grothe, who was also the team's leading rusher with 72 yards, finished 19-for-26 for 255 yards. His second touchdown pass in the third quarter was the 40th of his career, good for second in the history of South Florida.
Running back Ben Williams also had a 1-yard rushing touchdown, finishing with 25 yards.
South Florida pulled away in the third following a sack and a forced fumble by defensive tackle Aaron Harris and a recovered fumble by Craig Marshall. That set up a 2-yard touchdown pass from Grothe to A.J. Love.
After forcing a punt, the Bulls went up 34-13 after a 9-yard pass from Grothe to receiver Taurus Johnson.
Johnson, who had two touchdown receptions, had three catches for 29 yards.
The Bulls have outscored their opponents 59-7 in the third quarter this season.
Running back Curtis Brinkley was the Orange's lone bright spot, rushing for a team-high 117 yards on 21 attempts and a touchdown. It was his fifth 100-yard plus game of the season.
Quarterback Cameron Dantley struggled to get drives going in the second half, going 11-of-28 for 129 yards in the game.
The Bulls opened the scoring early in the first quarter. A 20-yard Grothe screen pass to Williams set up a 1-yard score by Williams on the next play.
Syracuse (1-6, 0-3) had a 43-yard field goal by Patrick Shadle on the next drive.
South Florida scored on its next drive with a 7-yard touchdown pass from Grothe to Johnson.
The Orange answered on the first play of the second with a 24-yard touchdown run by Brinkley, but Grothe added an 11-yard touchdown run.
The Bulls led 21-13 at the half following a 24-yard field golf by Shadle.
Bulls kicker Maikon Bonani added a 31-yard field goal in the fourth, and Richard Kelly had a 2-yard score late in the fourth.
All-American defensive end George Selvie, who has been nursing an ankle injury, made his first start since Sept. 27 at N.C. State. He finished with two tackles and a sack.
Linebacker Brouce Mompremier also started his first game since suffering a serious neck injury in the Sept. 20 win at Florida International, in which he had to be airlifted off the field. Mompremier finished with two tackles.