Andreas Johansson came in for Svetoslav Todorov and Emmerson Boyce replaced David Wright in defence.
Blackburn also made a number of changes and for the first 15 minutes they were all at sea against an eager Wigan outfit that started in tremendous fashion.
Brad Friedel made a great save to keep out a fierce drive from Josip Skoko as Wigan looked the better side in the opening stages, but it was the visitors who took a shock lead against the run of play after 36 minutes.
Wigan defender Leighton Baines was harshly adjudged to have brought down Morten Gamst Pedersen and the Blackburn player recovered to curl in a delightful free-kick which Wigan striker Emile Heskey glanced passed his own keeper.
The goal sparked the visitors into life and only a last-ditch tackle denied Shabani Nonda as Blackburn suddenly found time and space to launch their attack.
A rare Wigan raid was halted with a foul by Lucas Neill on the lively Dave Cotterill which earned the Rovers defender a booking and the same player was lucky not to be shown a red card for a foul on Emile Heskey.
Nonda could have doubled Rovers' lead right on half-time when a slip by Boyce let him in the clear, but Arjan De Zeeuw came to the rescue.
The limping Nonda was replaced by Matt Derbyshire at half-time while Wigan replaced Skoko with Wright and the home side almost drew level immediately after the restart when Heskey met Denny Landzaat's corner with a fierce header, only to see the ball scrambled off the line.
To make matters worse for Wigan, Rovers immediately went two goals to the good when Pedersen stole in at the far post to head Neill's superb cross into the path of substitute Derbyshire to tap into an empty net.
Wigan's humiliation was complete after 75 minutes when Benni McCarthy added a third from the penalty spot after Fitz Hall had handled a clever chip from the same player.