The Tigers led by as many as 16 points in the first half, but struggled early in the second period as the Commodores steadily overcame an 11-point halftime deficit.
Vandy caught the Tigers on a three-point field goal with 11:37 to play on a three-point shot by John Jenkins and Auburn was never able to regain the lead. The Commodores built their lead into double figures and were able to hang on to improve to 4-0 in the SEC.
Senior Lucas Hargrove led Auburn with 19 points and 10 rebounds. He hit 5-9 field goals and 8-9 free throws for the Tigers, who fell to 10-10 overall and 1-4 in the SEC.
It was a ninth straight win for the Commodores, who are 15-3 overall.
DeWayne Reed scored 16 points for the Tigers and Frankie Sullivan added 14.
Jeffery Taylor led the Commodores in scoring with 18 points and center A.J. Ogilvy added 17 points and eight rebounds.
Auburn hit 46.3 percent of its shots while Vandy made 53.7 percent. Auburn was 7-20 on threes while the Commodores made 5-15.
Vandy hit 19-25 foul shots while Auburn hit 17-24.
The Tigers held a 33-28 edge in rebounds, but turned the ball over 14 times, four more than the home team.
Lebo's Auburn team jumped out to a 20-10 lead and built the margin to 14 points when Reed hit a three-pointer from the corner with 5:38 left in the first half.
The Tigers increased the margin to 41-25 at the 3:10 mark as Hargrove hit a long-range three. Hargrove had a dozen points at the break and was a major reason for Auburn's lead at intermission, Lebo said.
By halftime the Commodores cut the margin to 43-32. Auburn built the lead by shooting 53.3 percent from the field and hitting 5-12 threes while also enjoying a 22-10 rebounding edge.
Lebo said he liked his team's effort, but he said that it looked Vandy, which had a week to prepare for the game, looked like the fresher team in the second half.
The Auburn coach said the key to Vandy's success was points in the paint in the second half. Auburn was outscored 32-10 in inside points in the second half and Ogilvy was a big part of that.
Lebo said another factor in Vandy's inside success in the second half was foul trouble on center Brendon Knox, who was in the game for just 12 minutes of action. "We need to get 28 minutes from Knox in a game like this," the coach said.
"Vanderbilt played well in the second half," Lebo said. "They scored at a high clip in the second half and got some easy buckets and kind of wore us down a little bit more than anything.
"I loved the way we played to start the game in the first half," Lebo added. "I thought we moved the ball well. We shot the ball well. We got high percentage looks. We defended pretty well. They are good. What makes them so hard to defend is they have nice balance. They can score inside, and they can score outside."
Auburn returns to action on Thursday with a home game vs. Ole Miss at 8 p.m.