Siemian was 31-44 and didn't throw an interception.
The win ended a seven-game losing streak for Northwestern (5-7, 1-7 Big Ten).
The Wildcats gashed an Illinois defense that has given up big yards and points all season. Northwestern's 560 total yards made it the fifth team to top 500 yards against Illinois (4-8, 1-7).
Illinois quarterback Nathan Scheelhaase was 31-45 for 307 yards and two touchdowns in his last game at Illinois. Scheelhaase threw one interception in the game, but it was a game-changer.
Down 30-27 with just over eight minutes to play in the game, Illinois was driving. On a first-and-10 at his own 45, Scheelhaase rolled right under pressure and, just before he stepped out of bounds, forced a ball down the sideline. The only player close to it was Northwestern defensive end Tyler Scott, who juggled the ball but held it with both hands as he went out of bounds.
The play was upheld on review, a decision the sparse crowd howled loudly about and coach Tim Beckman argued over with the officials.
The Wildcats made quick work of Illinois' defense, driving to the 7-yard line where Siemian found Jones in the end zone for the touchdown that put the Wildcats up by 10, 37-27, with 8:07 left to play.
Illinois pulled back to within three when Scheelhaase hit Miles Osei for an 11-yard touchdown with 2:23 left in the game.
But Northwestern's Cameron Dickerson came up with the onside kick and the Wildcats ran out the clock.
Scheelhaase, a four-year starter, finished his career at Illinois with 10,634 total yards, No. 1 on the team's all-time list. His 362 yards Saturday broke Juice Williams' old record.
But the Wildcats didn't need him. Siemian's passing yards and touchdown passes were both career highs for the junior.
Illinois opened the second half with a blast from running back Josh Ferguson, a 55-yard touchdown run that gave the Illini the lead, 24-20.
Ferguson finished Saturday with 110 yards and two touchdowns on 14 carries.
His run gave Illinois a solid shot of momentum that its defense put to good use.
The Illini held the Wildcats to just a field goal in the third quarter, and late in the period buried Northwestern at its own 2-yard-line with a 66-yard Justin DuVernois punt, almost a third of it on a big roll.
But Northwestern conjured up a ghost from one of Illinois' worst losses of the season to jump back into the lead.
Illinois' 42-3 loss to Michigan State was close until the Spartans battered the Illini with a 99-yard second-half touchdown drive that changed the game.
The Wildcats only had to go 98 yards, but they did. Siemian finished it with a 13-yard touchdown pass to Rashad Lawrence for a 30-27 lead with 14:55 left in the game.
The Wildcats took an early 10-0 lead and appeared to be in control.
Over a stretch of two and a half minutes early in the second quarter, though, Illinois stole the momentum and erased the lead.
First Scheelhaase hit Steve Hull on the unlikeliest of 25-yard touchdown passes, jumping to launch the ball over the Wildcats' defensive pressure and finding Steve Hull flat on his back in the front of the end zone. The receiver slipped as he appeared to adjust to the ball and fell, but the ball found him, landing right on top of him with 13:36 left in the first half.
Hull finished with 13 catches for 155 yards and a touchdown.
Then with 11:08 left in the half, Ferguson reached an arm into the end zone for another touchdown, hammering the ball to the ground as 300-pound defensive tackle Greg Kuhar pinned his body to the turf just shy of the goal line. Illinois was up 14-10.
But Northwestern came back and took a 20-17 lead into halftime.