Conner led the Panthers out of the tunnel and onto the field before the game, receiving a raucous ovation. More applause followed after he carried the ball on Pitt's first offensive play, a rush that lost 1 yard.
Conner finished with 17 carries for 53 yards and added 3 catches for 16 yards.
"It's not my first game," Conner said. "I know it's a comeback game, but it's felt like a regular-season football camp, really. My battle was already won. Beating cancer, everything else was a reward."
Conner scored on a 3-yard touchdown run with 7:08 left in the second quarter to give Pitt a 7-0 lead. He stiff-armed a Villanova defender the whole way and was mobbed by teammates upon reaching the end zone.
He also recorded his first career receiving touchdown on a 9-yard catch that gave the Panthers a 14-0 lead just before halftime.
"That first touchdown couldn't be any better, stiff-arm into the end zone right into the student section," quarterback Nate Peterman said. "It was an emotional moment."
The 2014 ACC Player of the Year, Conner announced in December that he had been diagnosed with Hodgkin lymphoma. The redshirt junior vowed all along to beat the disease and be ready for the Panthers' season opener, and he did just that after going through 12 chemotherapy sessions.
Conner earned multiple All-America honors as a sophomore in 2014, rushing for 1,765 yards and 26 touchdowns. His 2015 season ended in Week 1, when the 6-foot-2, 235-pounder tore the MCL in his right knee.
The Associated Press contributed to this report.