Sunderland pulled out a huge comeback performance to end their winless run in style, powered by four second-half goals.
A tense and nervy first half gave way to a firecracker second as Wigan took the lead thanks to a stunning strike from Mohammed Diame.
Asamoah Gyan equalised within three minutes and then the floodgates opened, with Henderson slamming home his first goal before Stephane Sessegnon won and converted a spot-kick.
Henderson, excellent in midfield, added a second 13 minutes from time before Franco Di Santo pulled a goal back for the visitors in the 90th minute.
Captain Lee Cattermole produced one of his best displays in a Sunderland shirt and set the tone on an afternoon when the hosts battled for every ball and showed great strength of character to recover from the blow of going behind.
But there was collateral damage for manager Steve Bruce as he lost Phil Bardsley, Danny Welbeck and Asamoah Gyan to injuries.
Nonetheless, the Sunderland chief will have been delighted with the effort and application shown by his side as they notched their first victory since late January.
Going into the game looking to end their winless run, Sunderland had the first half-chance when Welbeck's deflected shot was claimed by Ali Al Habsi.
However, the hosts were dealt a serious blow with just three minutes on the clock when Bardsley went down following a sickening clash of heads with Nedum Onuoha.
The defender lay motionless on the field for several minutes while receiving treatment from the club's medical staff before being stretchered off with an oxygen mask strapped to his face.
It was the last thing manager Bruce and his team-mates would have wanted to see.
Bruce introduced Anton Ferdinand and his players continued to press, coming close in the 24th minute as Ahmed Elmohamady crossed from the right and Gyan, craning his neck to reach the incoming low ball, headed just wide of Al Habsi's goal.
But the injury curse struck again moments later when Welbeck went down injured off the ball and was replaced by Steed Malbranque.
Sunderland - now featuring Sessegnon up front alongside Gyan - were on top but Wigan came close on the half-hour when Cattermole was robbed by Ben Watson and the ball fell to Hugo Rodallega, who brought a good save from Mignolet with a snapshot from the edge of the box.
The game featured plenty of effort but few chances of note as the first period finished goalless.
The Black Cats started the second with plenty of verve, coming close when Al Habsi turned a Michael Turner header onto the roof of his goal before Elmohamady saw a low drive deflected past the post.
But it was Wigan who took the lead against the run of play seven minutes into the half. Diame, scorer of a stunning strike at the SoL last year, popped up again when he lashed home a loose ball from 20 yards, leaving Mignolet with no chance.
Fortunately, Sunderland's response was immediate. A free kick was spread out wide to Malbranque and Gyan nearly took the roof off the Stadium of Light when he headed home the Belgian's inswinging cross at the near post from six yards out.
The goal was the Ghanaian's 10th of the season and his first since scoring in the home defeat to Spurs in February. It could also be one of his most important.
However, it was to be the striker's last contribution to the game as the injury bug struck again - the frontman pulled up when chasing a long ball and was stretchered off, another addition to the casualty list.
Sulley Muntari entered the fray with Malbranque moving up front alongside Sessegnon. The diminutive pair - an unlikely combination - gave Wigan a torrid time as Sunderland found top gear and blew away their winless run.
The goal Wearside was baying for eventually arrived on 63 minutes when Henderson triggered a huge release of emotion.
Muntari provided the catalyst with a neat ball across the box, but the approach play was all Henderson's own. The England international powered past three defenders and advanced on Al Habsi before powering an unstoppable shot inside the keeper's near post and into the roof of the net.
It was a huge goal from the youngster, who has been excellent since returning to the side following a brief spell on the bench.
And any tension inside the Stadium of Light evaporated four minutes later.
Sessegnon, playing his best game since moving to the club in January, probed at the visiting defence with a diagonal run across the box and was hauled down by Wigan captain Antolin Alcaraz.
A pressure penalty if ever there was one - but Sessegnon stayed ice cool to send Al Habsi the wrong way and roll the spot-kick into the corner to spark delirium on the terraces.
However, it was left to Henderson to round off an incredible spell of four goals in 14 scintillating minutes, with Sessegnon the creator.
The latter raced away onto a superb ball down the left flank and left the Wigan defence guessing before laying a lovely ball across the box for Henderson, who took a touch before dispatching coolly beyond a hopelessly exposed Al Habsi.
Muntari could have added a fifth late on but half-volleyed wide, and although sub Franco Di Santo pulled a goal back in the 90th minute when he slid home from close range, the late consolation couldn't dent the buoyant mood inside the SoL following a battling, and not to mention deserved, win.