Varnado, who set the NCAA career blocks mark his last game, followed that with his highest scoring total against an Southeastern Conference opponent this season.
Barry Stewart scored 18, Ravern Johnson 15, Kodi Augustus 13 and Dee Bost 11 for the Bulldogs (21-8, 9-5), who used a 21-7 run in the second half to break things open.
Devan Downey, the SEC's leading scorer, was held to 12 points, his lowest output in a league game this season. The Gamecocks (14-14, 5-9) have lost five in a row.
Mississippi State had reached the 20-win mark last time out. The Bulldogs had won their past three against South Carolina and this figured a cushy way to bolster its NCAA Tournament credentials.
But Mississippi State was up only 39-37 with 16:40 left after Downey hit a floater over the outstretched arms of the 6-foot-9 Varnado.
But the Bulldogs' shot-blocking machine showed off his offense next trip down to get the decisive run started. Augustus hit three foul shots and Stewart a jumper to make it 48-37 three minutes later.
Mississippi State wasn't done. Johnson added a 3-pointer and two foul shots and Stewart canned his fifth three of the game for a 60-44 lead. South Carolina couldn't get any closer than nine points the rest of the way.
It was one of the worst showings for Downey, who had dazzled opponents for most of the SEC season. In this one, though, he shot only 5 of 14 and missed all seven 3s he tried.
Sam Muldrow led the Gamecocks with 15 points. Ramon Galloway added 14.
Varnado increased his NCAA blocks mark, swatting back Muldrow's attempt with 6 minutes left.