Denny Landzaat, former Blackburn player Marcus Bent and Paul Scharner had given the Latics a three goal advantage by 37 minutes and had even seen Rovers Benni McCarthy's 22nd minute penalty brilliantly saved by Chris Kirkland.
At this stage Rovers had been reduced to ten men following the dismissal of Brett Emerton for two bookable by referee Mark Clattenburg.
Former Ewood Park striker Bent quickly restored Wigan's lead and went on to claim his own match ball with a decisive fifth in the closing minutes as Wigan won at home for the first time in six attempts.
Latics boss Steve Bruce reflected on his team talk before this extraordinary game. "Last words I said to them yesterday were, 'We can't concede three goals and win a football match - it's impossible'.
"That's what we've been conceding, unfortunately, and we've done it again today."
"The first half, apart from the last 10 seconds of the three minutes added on, was the complete performance from us," Bruce added.
"We were right up for the challenge and certainly blew Blackburn away in the first half.
"The goal from Santa Cruz gave them a lifeline and that was a big kick in the teeth. We got a bit edgy and a bit nervous.
"But in terms of attitude and application, terrific, and we need to show that again.
"I don't think we've had that intensity. They've worked extremely hard for the last couple of weeks to improve on that.
"It's been a difficult week after getting mauled at Bolton last week. But the response was terrific."
Bruce admitted he feared for his side after Santa Cruz plundered his third goal.
"I thought 'here we go, this is going to test a few'.
"To be fair to them, they've had a response again.
"They could have easily surrendered and thought 'well, this is not going to happen for us'."