After a scrappy game the defender rose highest to power in Max Power's corner and move the Latics into 22nd place, just two points from safety.
Wolves went close through Dave Edwards, but Wigan goalkeeper Matt Gilks produced a great save to palm the Wales midfielder's header away.
The hosts have now lost three straight Championship matches and stay 18th.
Going into the fixture Wolves had won just one of their last five league games at Molineux against Wigan and struggled to fashion chances despite enjoying 59% possession.
Bright Enobakhare threatened, but Paul Lambert's side lacked cutting edge in the final third and were punished late on from a set-piece.
Buxton headed in a first goal since February 2015 to put Wigan ahead from just their second shot on target and Gilks tipped over Connor Ronan's 30-yard effort to make sure of the points.
The victory sees Wigan move up one place past Blackburn Rovers, who suffered a 2-1 defeat by Sheffield Wednesday.
Wolves boss Paul Lambert:
"I'm like everyone else, disappointed and angry with the way that we performed.
"We never did enough, that's for sure; it wasn't good enough. We were too passive, we never dominated the ball and were not aggressive enough with or without the ball.
"Normally my teams come out of the traps and that is the disappointing thing. If you don't do things right then you will get beat. We have to be better than that."
Wigan manager Warren Joyce:
"It was a tough game against a good side and the game could have gone either way, but in the end we have ended up with three points and we have got that really through effort, endeavour, bravery and guts.
"We have had a few kicks in the teeth and it shows a lot of character to come to a place like Wolves and stand up to them with the backing that they have got from the supporters and the stadium here."
Match ends, Wolverhampton Wanderers 0, Wigan Athletic 1.
Second Half ends, Wolverhampton Wanderers 0, Wigan Athletic 1.
Corner,  Wigan Athletic. Conceded by Carl Ikeme.
Attempt saved. Gabriel Obertan (Wigan Athletic) right footed shot from the right side of the box is saved in the top right corner. Assisted by William Grigg.
Corner,  Wolverhampton Wanderers. Conceded by Matthew Gilks.
Attempt saved. Connor Ronan (Wolverhampton Wanderers) right footed shot from outside the box is saved in the top centre of the goal. Assisted by Hélder Costa.
Sam Morsy (Wigan Athletic) is shown the yellow card.
Offside, Wolverhampton Wanderers. Jón Dadi Bödvarsson tries a through ball, but David Edwards is caught offside.
Attempt missed. Hélder Costa (Wolverhampton Wanderers) left footed shot from the right side of the box is high and wide to the left. Assisted by Conor Coady.
Goal!  Wolverhampton Wanderers 0, Wigan Athletic 1. Jake Buxton (Wigan Athletic) header from the centre of the box to the bottom left corner. Assisted by Max Power with a cross following a corner.
Corner,  Wigan Athletic. Conceded by Richard Stearman.
Foul by Morgan Gibbs-White (Wolverhampton Wanderers).
Callum Connolly (Wigan Athletic) wins a free kick in the defensive half.
Andreas Weimann (Wolverhampton Wanderers) is shown the yellow card for a bad foul.
Foul by Andreas Weimann (Wolverhampton Wanderers).
Stephen Warnock (Wigan Athletic) wins a free kick on the left wing.
Substitution, Wolverhampton Wanderers. Andreas Weimann replaces Bright Enobakhare.
Attempt missed. Bright Enobakhare (Wolverhampton Wanderers) right footed shot from outside the box is too high. Assisted by Hélder Costa.
Attempt blocked. William Grigg (Wigan Athletic) right footed shot from the centre of the box is blocked. Assisted by Max Power.
Attempt blocked. Callum Connolly (Wigan Athletic) left footed shot from the right side of the box is blocked. Assisted by William Grigg.
Attempt missed. Jón Dadi Bödvarsson (Wolverhampton Wanderers) header from the centre of the box misses to the left. Assisted by Conor Coady with a cross.
Danny Batth (Wolverhampton Wanderers) wins a free kick in the defensive half.
Foul by Gabriel Obertan (Wigan Athletic).
Attempt missed. Max Power (Wigan Athletic) right footed shot from outside the box is high and wide to the right. Assisted by Jamie Hanson.
Substitution, Wolverhampton Wanderers. Conor Coady replaces Ben Marshall.
Corner,  Wolverhampton Wanderers. Conceded by Jamie Hanson.
Attempt saved. David Edwards (Wolverhampton Wanderers) header from the centre of the box is saved in the centre of the goal. Assisted by Connor Ronan with a cross.
Dan Burn (Wigan Athletic) is shown the yellow card for a bad foul.
Hélder Costa (Wolverhampton Wanderers) wins a free kick on the right wing.
Foul by Dan Burn (Wigan Athletic).
Foul by David Edwards (Wolverhampton Wanderers).
Callum Connolly (Wigan Athletic) wins a free kick in the defensive half.
Attempt blocked. Danny Batth (Wolverhampton Wanderers) header from the centre of the box is blocked. Assisted by Connor Ronan with a cross.
Corner,  Wolverhampton Wanderers. Conceded by Sam Morsy.
Attempt blocked. Dan Burn (Wigan Athletic) right footed shot from the centre of the box is blocked. Assisted by Max Power with a cross.
Corner,  Wigan Athletic. Conceded by Connor Ronan.
Corner,  Wigan Athletic. Conceded by Richard Stearman.
Substitution, Wolverhampton Wanderers. Morgan Gibbs-White replaces Lee Evans.
Substitution, Wigan Athletic. Gabriel Obertan replaces Omar Bogle.
Lee Evans (Wolverhampton Wanderers) wins a free kick in the attacking half.
Jake Buxton headed in a late winner to earn Wigan a vital league win over Wolverhampton Wanderers.