Michigan (5-2, 3-0 Big Ten) has won five straight since opening with losses to Appalachian State and Oregon.
The Boilermakers (5-2, 1-2) have lost in consecutive weeks after starting strong and rising to No. 23 in The Associated Press poll.
Hart ran for 102 yards, setting a school record with his seventh straight 100-yard game, but did not play in the second half after appearing to hurt his right ankle.
Michigan's 31-7 halftime lead perhaps helped make the decision to rest him for next week's game at No. 18 Illinois easier. Hart was not in uniform in the second half, but walked along the sideline without a limp as he smiled and laughed with teammates.
Brandon Minor, Hart's backup, limped off the field in the third quarter after he appeared to hurt his left ankle.
Michigan's third-string running back, Carlos Brown, scored twice to put the Wolverines ahead 48-7 early in the fourth quarter.
The Boilermakers scored two TDs in the final minute.
Chad Henne was 21-of-28 for 264 yards and two scores, both to Manningham, who had eight receptions for a career-high 147 yards. Manningham missed the previous game for an unspecified reason.
Purdue's Curtis Painter completed 17 of 28 passes for 113 yards, his lowest total since 2005, and two interceptions.
Painter ran for a 5-yard TD to tie the game midway through the first quarter, a play after Henne fumbled, then the Boilermakers were dominated on both sides of the ball.
Purdue hasn't won at Michigan Stadium since 1966 when Bob Griese was its quarterback.
The Boilermakers feasted on weak competition over their first five games, averaging 45 points and almost 500 yards, before being humbled in a 23-7 loss to Ohio State and embarrassed at Michigan.
The Big Ten powers shut down Purdue's running game, making its spread offense predictable and easy to stop. Kory Sheets was held to 20 or fewer yards rushing by the Wolverines and Buckeyes after running for at least 111 yards in the previous three games.
Hart, meanwhile, added to his bid for the Heisman Trophy with a made-for-TV play late in the first quarter. He ran to the left, landed on his back atop a teammate, rolled off, kept himself off the turf by extending his right arm and scored on an 11-yard run.