Siller passed for three touchdowns and ran for another in his first career start, and Orton lateraled to Desmond Tardy after a catch for the final score with 26 seconds left in the Boilermakers' 48-42 victory over slumping Michigan on Saturday.
Michigan's first losing season since 1967 ended any possibility the Wolverines had to extend their streak of 33 straight bowl appearances.
"I'm going to keep going back to work. What do you want me to say?" first-year coach Rich Rodriguez said.
"We're going to get up, go through the same routine. We're going to get up, work tomorrow, try to get better," he said "You want to look at the finality of it all? I've been here nine, 10 months. We've had great tradition; we still have great tradition, and we're going to try to do all we can to uphold it. But right now, we're not going to a bowl."
Michigan (2-7, 1-4), which has lost five in a row, tied the game at 42 with 1:20 to go on the third touchdown run by Brandon Minor.
But Siller quickly passed 18 yards to Keith Smith and 20 yards to Tardy, taking Purdue to the Michigan 35. After a 3-yard run by Siller, he passed 4 yards to Orton, who flipped the ball to Tardy for the go-ahead score.
"I usually line up at outside receiver," Tardy said. "But on this drive the coaches had me line up inside. Justin made a great throw, and there was a good pitch and catch, and I was lucky enough to get around the edge."
Purdue (3-6, 1-4 Big Ten) snapped a five-game losing streak and kept alive its chances for an 11th bowl bid in retiring coach Joe Tiller's 12th season.
"It was a great play call, first of all," Siller said of the game-winner. "G.O. caught the pass, gave a great pitch to Des and Des took it the rest of the way."
Michigan's desperation heave into the end zone with no time remaining fell harmlessly to the turf, sending the Wolverines to a school-record seventh loss.
The Wolverines, 0-3 on the road, finish at No. 20 Minnesota, at home against Northwestern and at No. 13 Ohio State. The Boilermakers, who need to win out to become bowl-eligible, play at No. 22 Michigan State and Iowa and finish at home against Indiana.
Orton also had a touchdown reception. Kory Sheets, who rushed for three touchdowns, had the third TD catch from Siller, who finished 21-of-34 for 266 yards passing.
Sheets rushed for 118 yards, and his four touchdowns tied his career high with the Boilermakers. It also was the most points by Purdue and the most combined points in the 54-game series with Michigan.
Tiller, who will be succeeded by associate coach Danny Hope next season, finished 2-6 against Michigan. His only other win over the Wolverines was 32-31 in 2000, the year Drew Brees led the Boilermakers to the Rose Bowl, when Travis Dorsch kicked a 33-yeard field goal with 4 seconds to go.
This time, Siller was the difference-maker.
"He played an outstanding game," Tiller said. "He did a nice job protecting the ball. I liked the decisions he made. I really liked his composure, and of course he brings an element of athleticism to the position that otherwise we don't have."
Siller, a 220-pound sophomore used primarily before as Sheets' backup at running back, ran for 77 yards on 15 carries Saturday, which was no surprise to Rodriguez.
The Wolverines expected Siller to be "just like he was today, that he'd run around and make plays," Rodriguez said. "We didn't do a good job keeping him contained, and we didn't do a good job of tackling him, and he made some plays."
Siller, a third-stringer until backup Joey Elliott had a season-ending shoulder separation two weeks ago and Painter went down with a similar injury last week, twice rallied the Boilermakers from 14-point deficits. Sheets' second touchdown run, a 3-yarder late in the second quarter, pulled Purdue within 28-21 at halftime, then a 35-yard pass to Orton set up Siller's 7-yard pass to Sheets that tied the game at 28 early in the third quarter.
The game was tied again at 35 after a 5-yard run by Sheets late in the third quarter and a 12-yard run by Minor early in the fourth quarter. Midway through the period, Purdue linebacker Anthony Heygood took the snap on a fake punt and ran 61 yards to the Michigan 7, and three plays later Siller hit Orton from 4 yards out for a 42-35 lead.
Minor's third TD run from 1 yard out tied the game for the final time.
Linebacker Myles Jack, who suffered a season-ending knee injury, said Thursday he decided to leave UCLA and enter the 2016 NFL draft because he wants to be compensated for his skills.
Randy Edsall will coach Maryland against No. 1 Ohio State on Saturday, the school announced Thursday as rumors swirled about his job status going forward.
Tennessee chancellor Jimmy G. Cheek has issued a statement amid rumors that alleges coach Butch Jones fought and punched senior offensive lineman Mack Crowder during a fall practice session.
With the addition of a few tweaks, UConn football coach Bob Diaco is still planning to bring a rivalry trophy with him to Florida on Saturday when the Huskies play UCF.
Arizona quarterback Anu Solomon will start against Oregon State on Saturday, a source told ESPN.
Rutgers receiver Leonte Carroo returned to practice Thursday after charges that he attacked a woman he used to date were dropped, and he said he was "lucky" to be playing again.