The loss sealed the first three-game sweep of the Rebels (24-20, 9-12 SEC) in conference play this season.
It was the fourth sweep of the season for the Gators (34-10, 17-4 SEC), who have won seven games in a row and outscored the Rebels 24-6. They hadn't managed a sweep against Ole Miss since 2002.
"You have to tip your hat to Florida," said Ole Miss coach Mike Bianco. "They played terrific and got the big hits to extend the lead. We stayed out of giving up the big inning, but we just couldn't stop them. Florida pitches well and their command is good, they got the big hits and make all the plays defensively. They just kind of smother you out there."
Ole Miss put men in scoring position in four of the first five innings, but couldn't get a run home until a Will Allen single in the seventh inning put the Rebels on the board. Matt Smith added a home run in the eighth inning to move into sole possession of second place on the all-time list for home runs at Ole Miss with 41 for his career.
Austin Wright (4-4) suffered the loss for the Rebels as he allowed four runs on five hits with a strikeout in 22/3 innings of work.
Florida's Karsten Whitson (6-0) held the Rebels scoreless through 6.0 innings and allowed three hits with two walks and four strikeouts.
"The thing that I'm most proud of with this team right now is the way they came out today and played," said Florida coach O'Sullivan. "Most teams would be satisfied with two wins and winning the series but the way they came out and swung the bats aggressively and played great defense was impressive."
Gators catcher Mike Zunino went 4 for 4 with three doubles and drove in four runs in the victory.
Zunino singles home a run in the first, then had two-RBI doubles in the third and fifth as the Gators built a 7-0 lead.
Ailing Ole Miss closer Jake Morgan saw his first action since March 20, giving up one hit in 11/3 innings of relief.
The Rebels visit Arkansas State on Wednesday night, then will entertain defending national champion South Carolina next weekend.