Led by senior guard Zach Graham, who scored a career-high 30 points after hitting 7-11 three-point field goal attempts, the Rebels made 56.8 of their shots to run away with the victory.
The Rebels improved their record to 17-9 overall and 5-6 in the SEC.
Auburn, which had played well in recent games, struggled almost the entire 40 minutes as the Tigers fell to 9-16 and 2-9 in the conference.
Auburn's previous worst loss was a 78-54 setback at Kentucky on January 11th.
"It was one of those nights when everything that could go wrong went wrong," Auburn coach Tony Barbee said.
Chris Denson was Auburn's only double-figures scorer as the freshman guard finished with a collegiate high point total of 16.
The Rebels jumped to a 10-0 lead to start the game. The Tigers cut the lead to 15-13, but Ole Miss made a 19-5 run to close the half and was never threatened after that.
"We played good defense and had them stuck on 15 for five and a half minutes," Barbee said. "For five and a half minutes we got stops, we just couldn't score.
"We are what we are and eventually against a very good offensive team, like Ole Miss is, you are not going to stop them like that the entire game," Barbee said. "They are eventually going to break free for a couple of shots.
"All of a sudden a two-point lead goes to 12 and against a team that scores the way they do it makes you get aggressive and then you are over-aggressive and fouling and they are the second best free throw shooting team in the country."
Ole Miss burned the Tigers at the free throw line making 27-32. Auburn made 14-21 of its free throws and hit 41.2 percent of its field goals, including 3-15 threes.
The Rebels were particularly tough from long range making 13-25 three-pointers.
Chris Warren scored 15 points for the Rebels and Terrance Henry added 14.
Ole Miss won the rebounding battle 33-26 and each team finished with 17 turnovers.
The Tigers return home for their next game. Vanderbilt, ranked 18th, will be at the Auburn Arena for a 3 p.m. tipoff on Saturday. Vandy, a winner over Georgia on Wednesday night, improved to 19-6 overall and 7-4 in the SEC.