The Cincinnati Bearcats played its first ever game as a member of the American Athletic Conference.
It was Purdue's worst opening game loss since 1996 when Michigan State beat them 52-14.
Cincinnati is now 80-38-10 all-time in season opening games.
Cincinnati starting quarterback Munchi Legaux threw an interception on the first offensive play of the year.
That play immediately followed an interception by Nick Temple on the Bearcats first defensive series of the season.
Purdue had a first and goal at Cincinnati's five yard line and it looked like the Boilermakers' day, but B.J. Knauf was thrown for a two-yard loss by Jordan Stepp and Jeff Luc. Purdue quarterback Rob Henry was sacked for an 8-yard loss by Silverberry Mouhon. Henry fumbled but Purdue recovered on the 16. A delay of game penalty pushed Purdue back to the 22 yardline.
Paul Griggs missed a 39-yard field goal attempt.
Purdue's first year coach Darrell Hazell brought in a new offense. Purdue had problems executing it the entire game.
"We didn't execute in all phases," Hazell said. "We had communications problems We took too long in the huddle which caused us to rush."
Legaux sprinted into the endzone from 10 yards out with 13:39 left in the second quarter.
The teams played evenly for 10 minutes but Purdue broke through with a score with 3:26 left in the half.
With Purdue pinned down on a fourth and 17 on its own five, Cody Webster launched a 73-yard punt that Anthony McClung had to sprint toward his own goal line to field. The punt was off his fingertips and Jesse Schmitt won the scramble for the loose ball at the Cincinnati 11.
Akeem Hunt picked up four yards. Henry scored Purdue's only points of the game with a 7-yard run.
Legaux led UC on a 75-yard drive in seven plays, completing a 15-yard touchdown pass to Blake Annen with 17 seconds left.
The Bearcats turned the game into a rout the second half, scoring two touchdowns in each quarter.
Ralph David Abernathy IV seored on a 3-yard run midway through the third quarter. Two minutes later Adrian Witty returned an interception 41-yards for a touchdown.
Purdue managed just 33 yards of offense in the third quarter.
"We only ran 60 plays all game," Hazell said. "We had too many three and outs."
Hosey Williams, a junior college transfer from Miami, Florida, scored on a 30-yard run with 13:31 left in the game. Tion Green, a sophomore from Sanford, Florida capped the scoring with a 1-yard run with 6:50 left. Brendon Kay's 51-yard pass to Chris Moore set up the score. Green carried the ball for 27 yards on four straight runs.
Purdue's last drive of 54-yards in nine plays ended on a fourth and nine, incomplete pass.