Matthew Brinson tied the game in the third with a two-run single off USC starter Gary Bell (4-1) and Steve Gendron drove in another run in the inning to give the Bulldogs a 3-2 advantage.
Jon Mungle belted his third home run in as many games and the fourth of the year to give the Bulldogs a 4-2 lead in the fourth inning.
State chased Bell from the game with a three-run fifth inning burst helped along by four walks. Enrico Jones doubled in one run and Chad Henry singled in two more in the inning and in the sixth Jones added a two-run single for a 9-3 MSU lead.
The Bulldogs closed out the scoring with a three-run, four-hit eighth inning spree highlighted by a two-run double by Matthew Maniscalco.
The route-going pitching performance was the first career nine-inning mound stint for Maholm and MSU's second complete-game of the season.
Mungle and Henry collected three hits each and Henry and Jones drove in three runs each to pace the Bulldogs' 14-hit outing. Henry and Gendron extended their career-best and team season-best hitting streaks to 10 games.
Trey Dyson had a double and a home run for South Carolina.
The teams continue their three-game series Saturday at 2 p.m. at Dudy Noble Field. Senior righthander Tanner Brock (3-0, 2.37) will start for the Bulldogs opposite USC sophomore lefty David Marchbanks (4-1, 2.37). The game will be broadcast on the MSU Baseball Radio Network.
MISSISSIPPI STATE 12, SOUTH CAROLINA 4
MSU (10-4-1) 003 132 03x - 12-14-0
WP - Paul Maholm (3-1). LP - Gary Bell (4-1). HR - (USC) Yaron Peters (8), Trey Dyson (5), Brian Buscher (4); (MSU) Jon Mungle (4). T - 2:35. ATT - 1,477 (actual), 6,096 (paid).