Will Grigg struck twice to send Wigan past 10-man West Ham and into the fifth round of the FA Cup, with Arthur Masuaku sent off for spitting.
Masuaku was sent off early in the second half of the Hammers' 2-0 loss at the DW Stadium when he spat at Latics forward Nick Powell.
League One Wigan, winners of the FA Cup in 2013, followed up their elimination of Bournemouth in the third round by beating another Premier League opponent thanks to goals in either half from Grigg.
Their victory came after visiting boss David Moyes stated he believed Wigan fans would have traded their cup success five years ago for Premier League safety, having been relegated three days after beating Manchester City at Wembley.
He might have reconsidered that view shortly after kick-off as a Wigan side featuring just one change raced out of the blocks in front of a pumped-up crowd.
The hosts took the lead after just seven minutes from their first attempt on goal, as Nathan Byrne's deep cross from the right was nodded by Grigg beyond Joe Hart and into the top corner.
At such point-blank range, there was little Hart could do but watching England boss Gareth Southgate would have noticed Chey Dunkley squeeze the ball past him moments later - only for the offside flag to deny Wigan a second.
Moyes had made six changes for the contest and his midfield lost its most experienced figure when Pedro Obiang suffered a suspected knee injury from Max Power's sliding tackle.
Obiang immediately indicated he was in some distress and left on a stretcher as Moyes introduced Reece Oxford to the action.
Wigan were well on top but might have conceded an equaliser had Sam Morsy not brilliantly blocked from Javier Hernandez after Antonio Martinez dispossessed Dan Burn near the byline.
Moyes handed a debut to Joao Mario for the second half, the day after he signed on loan from Inter Milan, yet the Hammers were soon down to 10 men.
The flashpoint occurred when Powell challenged Masuaku near the touchline. The former Manchester United forward continued to stare at his West Ham counterpart and, as Powell started to walk away, Masuaku spat in his direction.
Masuaku did not exit quietly once referee Chris Kavanagh had brandished the red card, with Powell and Grigg involved in heated confrontations as the temperature rose.
West Ham had provided little evidence they would get back into the game and after Grigg flashed a header from a Callum Elder cross wide, Wigan were awarded a penalty to kill the game just after the hour.
It was Grigg who won it when he attempted to flick the ball beyond Burke and appealed for a handball decision that he was granted.
The Northern Ireland international slotted his spot-kick straight down the middle while Hart flung himself to his left to double Wigan's advantage.
The lively Powell should have added a third when Byrne's cross narrowly evaded him with West Ham, who also lost Martinez to injury, beaten.
The managers
David Moyes (West Ham): "Ultimately, Arthur, what he's done, was despicable. He will deserve everything he gets and he will get something off us as well. It's unacceptable, totally unacceptable. The referee (Chris Kavanagh) doesn't see it and can't see it. So it was the players' reaction that got him sent off. Ultimately they got the right decision so I can have no qualms about it."
Paul Cook (Wigan): "We played well, great credit to our players. The game had a massive, defining moment. The sending off in the game was huge, in my opinion it altered the course of the game in relation to us, having a more positive effect on us. I don't think West Ham could sustain putting us under pressure and the game panned out a certain way."