The Bearcats (14-4, 4-1 Big East) took the ball inside down the stretch, converting a pair of three-point plays to take the lead for good with 5 minutes left.
Villanova (8-10, 1-5) remained winless on the road this season despite a career-best performance from its point guard. Wayns had 19 points in the first half, when the Wildcats shot 64 percent from the field and led by as many as 10. He finished with a career-high 13 rebounds.
Wayns' driving basket cut the lead to 81-78 with 6.6 seconds left. Cashmere Wright was fouled on the inbound play and made the first free throw to seal it.
Yancy Gates had 16 points and nine rebounds for Cincinnati, off to its best start in league play since it joined in 2005-06.
Cincinnati's defense is ranked second-best in the Big East, but couldn't handle Villanova's outside shooters in the first half. Wayns made seven of his eight shot, and the Wildcats - one of the league's worst 3-point shooting teams - went 10 of 16 from behind the arc while surging to a 45-40 halftime lead.
Villanova couldn't keep it up. The Wildcats shot only 28 percent in the second half, allowing Cincinnati to catch up and nudge ahead. The Bearcats made 6 of 8 free throws in the final 28 seconds, including four by Wright, who was only 2 of 14 from the field.
Cincinnati had only three turnovers in the game, preventing Villanova to get the fast break baskets that are a staple of their offense. Villanova's Dominic Cheek had 16 points in the first half but finished with only 19, missing five of his six shots in the second half.
Cincinnati has won nine of its last 10, including a 68-64 victory at No. 11 Georgetown on Monday set up by tough defense. The Bearcats forced 17 turnovers and had 13 steals against the Hoyas, relying on the one constant during their recent streak.
That defense struggled at the outset on Saturday.
Villanova was second-to-last in 3-point shooting in the Big East, making only 24.7 percent, but found its touch to start the game. The Wildcats made 4 of 5 from behind the arc to open the game, pulling out to a 16-6 lead that forced Cincinnati to call a timeout and regroup.
The Bearcats also came out firing away.
Dixon made four 3s during a 22-5 run over the next 4 minutes that pushed it to 28-21. The Bearcats made six consecutive 3s during the spurt, with Dixon leading the way. He hit his first five shots overall, four of them from behind the arc.
Wayns hit back-to-back 3s during a 14-3 run that closed the half and put Villanova up 45-40. Wayns also opened the second half by hitting another 3 for an eight-point lead.
The run-and-gun pace stuck, with both teams shooting away. Villanova cooled off fast, making only 3 of 15 shots to start the second half. Cincinnati couldn't do anything consistently, either, resulting in five quick lead changes.