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Danny Hylton and Cameron Jerome hit Luton Town's second-half goals to move the Hatters up to eighth in the Championship, two points off the play-off places.
On his second return to the Bet 365 Stadium since being sacked in November 2019, after just 10 months in charge, ex-Potters boss Nathan Jones had a much happier night.
But Luton still had to endure a fraught finale when Lewis Baker curled home a beauty to pull one back two minutes into injury time.
Luton had just gone close on the break when Harry Cornick got down the right and pulled back into the danger zone, only for Joe Allen to slide in and deny Allen Campbell with a superb cover tackle.
But when Cornick got into the same area three minutes later, Stoke had no answer as Hylton arrived at the near post to drill home as the 581 away fans celebrated wildly.
The Hatters could have twice stretched their lead through top-scorer Elijah Adebayo on the break before Jerome settled the outcome with eight minutes left.
Former Chelsea youngster Baker's stunning right-foot curler - his fourth goal in seven games - gave Stoke late hope but Luton's second-half display warranted victory.
Stoke striker Tyrese Campbell had the only first-half effort on target
After a really poor first half, in which Stoke striker Tyrese Campbell had the only effort on target, Luton visibly upped their game after the break, just as they did against West Bromwich Albion on Saturday.
It was no surprise when Hylton capped off that pressure by sliding in for only his second goal of the season - and his first for five months.
And 12-goal top-scorer Adebayo had two great chances to double their lead, being denied first by the outstretched left arm of home keeper Joe Bursik, then again when he dithered too long and on-loan Man City defender Taylor Harwood-Bellis got back to block.
Jerome then settled it when Kai Naismith swung the ball in from the left and the former Stoke striker shook off his markers to steer home a decisive left-foot finish.
It was his second goal in successive games, having not previously scored in the league for Luton - and a fitting way to mark his own return to the Potteries following three fairly fruitless seasons there a decade ago. But it was Jones' night - and he celebrated wildly in front of the Hatters fans on his way to the exit.
Stoke old boy Cameron Jerome followed up his first league goal for Luton against West Brom at Kenilworth Road on Saturday with what proved to be Luton's clinching second
Going into Saturday's trip to Bournemouth, Michael O'Neill's Stoke are now 14th, nine points off the play-offs, after their fifth defeat in a run of just two league wins in 10 games since Christmas.
Luton, who host Wayne Rooney's Derby, are now firmly in the pack of clubs chasing the four play-off places - a battle that currently sees just six points covering seven clubs - and the Hatters are only seven points off an automatic promotion place.
Potters boss Michael O'Neill told BBC Radio Stoke:
"It didn't happen for us in the second half. We looked disjointed. Miles away from where we need to be.
"We gave away a poor goal. We gave them something to hold on to and the game got bitty.
"There were a number of players who were short of where we'd expect them to be and we have to look at that. We need more belief and confidence."
Hatters boss Nathan Jones told BBC Three Counties Radio:
"That's as good as it gets. We showed quality and real fight. It's phenomenal for a club of this size to win like that at a place like this.
"I'm very proud, not because it's my old club but because of the way we played. I could sense the crowd turn and we grew into the game.
"We took control second half and without being disrespectful we should have had more."
