Stephen Garcia passed for 228 yards and Marcus 3, at Williams-Brice Stadium.
Garcia completed 16-of-30 passes and was intercepted four times, but the Gamecocks (4-0, 2-0 SEC) still opened the year with four straight wins for the first time since the 2001 squad went 5-0.
"Our defense came to play tonight. That was by far our best game of the year," said South Carolina head coach Steve Spurrier. "Our offense sputtered around most the game, had a bunch of penalties after some big plays here and there. Glad we had good defense tonight, because the offense did very little."
Lattimore finished with 77 yards on 20 carries, adding 73 yards on three catches for South Carolina, which held its foe to 77 total yards of offense.
Larry Smith was 12-of-16 but threw for 44 yards and one pick for the Commodores (3-1, 1-1).
Jonathan Krause totaled nine catches for 55 yards in the setback.
South Carolina's defense spurred its initial score of the contest.
Early in the second quarter, Smith was hit and sacked on a 3rd-and-7 from his own 39, and coughed up the football. It was recovered by Antonio Allen at the visitors' 31, but when he fumbled at the 10 on the run back, Melvin Ingram picked it up and stepped into the end zone for a 7-3 advantage.
Garcia later found Lattimore for a 52-yard touchdown strike with 13 seconds to play in the quarter and the Gamecocks led 14-3 at the break.
After holding the Commodores to a three-and-out on the first drive of the second half, Lattimore posted a 22-yard scoring run on South Carolina's first possession to make it 21-3, and the defense shut down Vanderbilt from there.
Vanderbilt's remaining possessions ended on four punts, and another Smith fumble on a sack. None of those drives saw the Commodores reach past their side of the field.
"I thought our defense played extremely well. I think they played good enough to win. They picked off Garcia four times. We got a long ways to go, we got a lot of work to do, no different than what I've been saying each week and we faced a talented team tonight and it showed," admitted Vandy head coach James Franklin.
Carey Spear's 33-yard field goal put Vandy on the board and was the lone score of the opening quarter.
South Carolina has won 17 of the 21 all-time meetings...The Gamecocks claimed a 131-4 advantage on the ground and a 367-77 edge in total yardage...Both schools continue their respective conference slates next Saturday, as the Gamecocks host Auburn, while Vandy travels to Tuscaloosa to face Alabama.