Wilson scored on runs of 69, 68 and 45 yards while breaking Robert Baldwin's 20-year-old single-game record for the Blue Devils (3-0).
Anthony Boone threw two TD passes to Max McCaffrey for Duke, which scored the first three times it touched the ball, built a 511-297 advantage in total yardage and cruised to its first 3-0 start since 1994.
Boone finished 19 of 33 for 180 yards in three quarters with scoring passes to McCaffrey covering 36 and 10 yards. He improved to 13-0 as a starter in regular-season games.
The Jayhawks didn't advance farther than the Duke 17 and lost their 25th straight road game.
This was the 15th in that stretch by at least 20 points.
It marked the return trip of a series that started when these teams were on opposite ends of the college football food chain. Back in 2009, Kansas wasn't far removed from its Orange Bowl run when the Jayhawks earned a 44-16 rout of a doormat Duke team.
Five years later, and the roles have reversed drastically. It's the ACC Coastal Division champion Blue Devils who are conference contenders while the Jayhawks face a long road to respectability.
They struggled to get out of their own way as they slipped into a deep early hole they couldn't escape, falling behind 17-0 in fewer than 10 minutes.
And they couldn't stop Wilson. Not when the game was in the balance, and certainly not in garbage time.
On his first carry, he burst through the line and raced untouched through the left side on his way to a 69-yard touchdown run - his first college TD - that pushed the lead to 17-0.
His second college score was only slightly shorter - a 68-yarder in the final minute of the third quarter made it 34-3.
Wilson then scored from 45 yards out to make it a 38-point game and bring him to 237 yards rushing - a yard shy of Baldwin's mark he set against Maryland.
He broke the record with an 8-yard run on the game's final play.
Boone capped Duke's opening drive by finding McCaffrey over the middle and the receiver broke two tackles on his way into the end zone to make it 7-0.
The two hooked up again on the second drive of the third quarter, with McCaffrey's shorter scoring catch making it 27-3.
Kansas' only points came on Matthew Wyman's 34-yard field goal late in the first quarter.
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