Kenny Miller fired Derby County in front midway through the first half, but it was one-way traffic towards Roy Carroll's goal from then on.
Santa Cruz levelled on the stroke of half-time, before Jason Roberts stroked the hosts ahead two minutes after the break.
And after a string of missed chances, Rovers' Paraguayan striker sealed the win with his 19th Premier League goal of a stunning first season in English football.
Blackburn boss Mark Hughes stuck with the same side for the fourth game in a row, while Derby, who included ex-Rovers Robbie Savage, Andy Todd and Jay McEveley in their starting line-up, made numerous changes to the side that lost 6-2 to Arsenal on Monday night.
After a slow start, the game sprung to life on eight minutes when Brad Friedel's hurried clearance struck Derby striker Robert Earnshaw, but the ball rebounded just wide of the mark.
But against the run of play, the visitors took the lead when Carroll claimed a Rovers corner before quickly launching the ball up field to Miller.
The Rovers defence stood still appealing for offside, but the Scottish striker had run from inside his own half before controlling the ball and coolly slipping it past Friedel into the back of the net.
Rovers responded well but without really testing the Derby keeper.
On 23 minutes, Brett Emerton's long-range effort deflected just wide of the post and captain Ryan Nelsen headed over the bar from the resulting corner.
Ten minutes later, David Bentley's audacious chip had to be tipped over the bar and, moments later, Carroll made a simple save from Chris Samba's header.
But on the stroke of half-time the equaliser finally arrived.
Morten Gamst Pedersen's crisp drive was parried by Carroll and Santa Cruz supplied the left-foot finish on the follow-up.
Buoyed by the goal, Rovers came out all guns blazing at the start of the second and took the lead less than two minutes in.
Following a mix-up in the Derby defence, Todd ended up playing in Roberts who tucked the ball into the corner of the net.
Rovers were in complete control but again lacked the cutting edge in front of goal.
However, on 77 minutes, Rovers did extend their lead when Bentley dinked the ball over from the left and Santa Cruz headed home at the far post.
Derby's defeat - their 28th of the season - means that they will go down to the Championship with the lowest points total in Premier League history.