McCulloch, who headed the winner at Manchester City last week, struck with an unstoppable right-foot shot which flew in from 25 yards - his fifth goal of the season.
But the lead was short lived with the Hammers levelling early in the second half when Marlon Harewood cashed in on a defensive mistake to claim his 15th of the campaign.
And Reo-Coker struck at the death to complete a smash-and-grab and dent Wigan's hopes of Europe next season.
Fresh from clinching a place in the semi-finals of the FA Cup, West Ham were looking to get back to winning ways in the Premiership at one of their lucky grounds.
In three previous visits, they had won two and drawn the other, and striker Dean Ashton in particular had good reason to remember his last game at the JJB Stadium.
Back in his Crewe days, the £7million man scored a hat-trick - something no other visiting player has ever done.
The Hammers were missing Christian Dailly, while Teddy Sheringham, a week away from his 40th birthday, was on the bench.
Wigan's only change was the return of goalkeeper Mike Pollitt among the substitutes after recovering from a hamstring injury.
The first threat came from the Latics. Skipper Arjan de Zeeuw sparked it with a telling ball to Henri Camara, which he flicked on to Jason Roberts who swept it wide for Gary Teale to hammer in a powerfully struck shot which Shaka Hislop did well to hold.
Wigan's John Filan - who took a knock early on and was replaced by Pollitt at half-time - was almost embarrassed when Paul Konchesky chanced his luck from long range. It had the keeper anxiously scrambling across his line before the shot whistled just wide of the left post.
Right-back Pascal Chimbonda halted a driving run by Ashton with a textbook tackle as the big striker headed for goal.
Then Hislop again proved up to the challenge when tested by a Jimmy Bullard free-kick fired in from 25 yards. It dipped just in front of the keeper, but he held it at the first attempt.
There was more danger when Camara used his speed to give James Collins the slip, but Hislop was quick to react and get the ball clear.
Roberts was just off target after stretching to get in a shot on the turn, and Wigan wasted a chance when Teale raced clear on the right but failed to pick anybody out with his cross.
The Latics were kicking themselves again when Roberts got the better of Konchesky but his pass was too deep, missing Camara and Bullard.
There was a let off for Wigan when Filan raced out of his area and collided with Chimbonda gifting a chance to Matthew Etherington. But the angle was difficult, and he failed to hit the target, much to Filan's relief.
Strike partners Harewood and Ashton teamed up to set up Reo-Coker, but his shot was blocked by Leighton Baines.
The deadlock was almost broken four minutes before half-time when McCulloch cracked in a terrific shot, but Hislop was there to keep it out.
The Hammers keeper, however, was powerless when Wigan snatched the lead in first-half stoppage-time. Bullard squared the ball to McCulloch and the Scottish star smashed it in from 25 yards with his right foot.
Camara should have made it two but failed to beat Hislop and Wigan were caught on the counter.
Scharner attempted to head the ball back to Pollitt but Harewood was alert to the opportunity and nipped in to virtually walk the ball into the net.
The Austrian almost made amends with a header at the other end but it was cleared off the line by Lionel Scaloni.
Hislop came to the rescue again by keeping out a McCulloch piledriver before substitute David Thompson headed another wide.
Wigan were made to regret the misses when Sheringham, with just seconds left to play, played a neat ball to Reo-Coker to net the winner.
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