Stanford (2-0) won its 10th straight game dating to last season and claimed a rare regular-season win on the East Coast while denying the Blue Devils (0-2) their first Top 25 win since 1994.
Lee Butler returned an interception 76 yards for a touchdown to pull Duke to 10-7 late in the first half. Luck then led four straight touchdown drives to turn it into a rout before exiting one play into the fourth quarter.
Owusu finished with seven catches for 106 yards and Jeremy Stewart added a 30-yard touchdown run for the Cardinal, who were making their fifth regular-season trip east since 1997.
Stanford was 1/3 in its previous four visits East since 1997, though the Cardinal did rout Virginia Tech in the Orange Bowl in January. Two years ago, they were beaten at Wake Forest in the first road start of Luck's career, a defeat that still rankles several upperclassmen.
In this one, Stanford methodically pulled away from a Duke team that was a three-touchdown underdog and was coming off another loss to a lower-division FCS team.
Even though the end result was the same, Duke barely resembled the outfit that lost to Richmond for the third time in six years.
Coach David Cutcliffe pulled out all the stops in his attempt to deliver the Blue Devils' first victory over a top 10 opponent since 1989 and first against a nonconference top 10 team since they beat then-No. 10 Stanford in 1971.
Duke faked a punt on a fourth-and-7 while trailing 10-0 midway through the second quarter. The gadget play worked -- Alex King floated a swing pass to Jay Hollingsworth for 21 yards -- but it only led to one in a frustrating series of missed opportunities when the outcome was still in doubt. Normally trusty Will Snyderwine missed his second field goal of the day.
Then, after Butler's pick-six pulled Duke to 10-7, Cutcliffe dialed up an onside kick that was recovered by Walt Canty at the Stanford 40 with about 2 minutes left in the half.
The game essentially swung on what happened next: Duke netted minus-14 yards on that drive, which ended with a 13-yard punt.
Then, Luck took over. The 2010 Heisman Trophy runner-up led Stanford 59 yards in four plays and capped the drive by hitting Owusu with a catch-and-run that made it 17-7 with 39 seconds left before halftime -- the first of five straight touchdown drives for the Cardinal.
Luck stretched the lead to 24-7 when Fleener beat safety August Campbell to the ball and rumbled downfield for his second score of the day. After Stewart's scoring run, Luck hit Ertz with a short strike that made it a 37-7 one play into the fourth quarter.
Fleener's first touchdown catch was a short flip from Luck that capped Stanford's opening drive. The Cardinal later went up 10-0 on Jordan Williamson's 40-yard field goal early in the second quarter.
Sean Renfree finished 19 of 27 for 179 yards for Duke.