Arnett Moultrie scored 18 points, Dee Bost 60 win over Ole Miss on Thursday.
Renardo Sidney added 14 points and Rodney Hood scored 10 for the Bulldogs (19-5, 6-3 SEC), who have won four of their last five.
Reginald Buckner had 15 points and nine rebounds to lead Ole Miss (14-9, 4-5) and Jarvis Summers scored 12.
The Rebels, after snapping their five-game losing streak to Mississippi State at home last month, never led in this one.
Mississippi State scored the first eight points of the game as part of a 16-4 run, including the first six on set plays in the paint. Sidney scored four, opening the game with a dunk as the home crowd was still in the midst of its pregame chants.
Brian Bryant's layup in transition made it 8-0. Hood scored the next eight points for Mississippi State, capping the run with a three from the left side.
"I was proud of how our kids came out from the get-go. We played really focused," said Bulldogs coach Rick Stansbury.
Later, after Ole Miss started to creep back into the game, Bost's alley-oop pass to Moultrie from around halfcourt gave Mississippi State a 38-27 lead and sent the Humphrey Coliseum crowd into a frenzy.
Moultrie's dunk off Bost's bounce pass in the lane gave the Bulldogs a 40-27 lead at halftime, and Ole Miss was never within single digits in the second half.
"I thought they came out and knocked us right down," said Ole Miss coach Andy Kennedy. "We showed signs of life at times (but) we didn't do a good enough job of containing."
Thursday was the 245th meeting between the two programs. Mississippi State has a 139-106 advantage...The Bulldogs have won 13 straight at home and haven't been swept in a season series by Ole Miss since 1998.