DePauw (1-4, 0-2) struggled offensively as freshman quarterback Justin Murray made only his second career start.
"We're young," interim head coach Scott Srnka said. "We're going to have to find ways to win and manufacture ways to win as we grow."
Ohio Wesleyan (5-0, 3-0) entered the game with a top-20 rushing defense nationally and lived up to the projection, holding DePauw to only 34 yards on 32 carries.
The Tigers defense, which struggled early, began to step up after giving up a 14-point first quarter.
"If we don't spot them 14, we're OK," Srnka said. "I told the guys, all (the difference) was one more play. One more play on offense. One more play on defense."
OWU junior quarterback Mason Espinosa threw for 346 yards and two touchdowns, though 261 yards -- and both scores -- came in the first half.
Down 14-3 in the second quarter, DPU freshman punter Paul Simon pinned the Battling Bishops at their own 13 and began to change the games momentum.
Two false starts, and a sack by junior Michael McManis, pushed them back to their own five-yard-line.
A snap over the head of the OWU punter went out of bounds for a safety.
Senior Taylor Wagner then returned the ensuing kickoff for a touchdown and brought DPU to 14-12.
On the next play from scrimmage, OWU sophomore running back Kevin Herman lost a fumble and gave the Tigers the ball at the OWU 39 with 10:48 left in the second quarter.
The offense failed to capitalize on the momentum as they were held to a punt.
Murray finished the game 21-of-46 for 164 yards and four interceptions.
Tigers quarterback coach Brett Dietz said Murray played like a freshman.
"We knew there'd be days like this," Dietz said. "I knew this was coming, because I've played college football before. You're a freshman. You don't know how to pick yourself up."
Dietz, in his third year as a coach at DePauw, played quarterback for Hanover College.
"It's hard to get game experience in practice, or they'd have been doing it for 100 years," he said. "He's a hardnosed kid, and that's why I was a little surprised at his reaction today."
Srnka said he expects starting quarterback Drew Seaman back next week when the Tigers play at Allegheny.
Although the offense struggled, Srnka said the defense stepped up the way he expected.
"We played it pretty well and got good pressure with four," he said. "We decided at half time to go after him a little bit more and that's what helped us in the second half."
DPU held the Battling Bishop to three points after halftime, but couldn't put together enough offense to capitalize.
- Taylor Wagner, who returned a kickoff for a touchdown in the second quarter, entered the game fourth among active NCAA Division III players in career punt return yards. OWU kicked away from him for most of the day.
- Saturday was Old Gold Day for DePauw, the school's version of homecoming. The Tigers are now 66-36-3 on Old Gold Days.
OWU -- Scott Jenkins 2-yd run (Miles MacKenzie kick good 10:09
DPU -- Eric Malm 32-yd FG, 7:34
OWU -- Nick Ziegenbusch 66-yd pass from Mason Espinosa (MacKenzie kick good), 5:58
DPU -- Team safety 11:19
DPU -- Taylor Wagner 86-yd kickoff return (Malm kick good), 11:00
OWU -- MacKenzie 33-yd FG :35
OWU -- Dave Moglinicki 46-yd pass from Espinosa (MacKenzie kick blocked) :18
DPU -- Myron Burr 20-yd fumble recovery (Malm kick good) 14:17
DPU -- Malm 34-yd FG 7:25
OWU -- MacKenzie 26-yd FG 1:08