Santa Cruz took two minutes to equalise and Derbyshire 60 seconds to stun the home crowd by giving the visitors the lead.
Middlesbrough were much the more dangerous side in the first half, but Rovers stepped up the pressure after the break to once again prove a bogey side to Boro.
Jeremie Aliadiere had an early chance to put Boro ahead, but the former Arsenal player put wide from close range.
Benni McCarthy thought he had put Blackburn ahead but he was flagged for offside.
Middlesbrough central defender David Wheater sent in a strong header that brought a brilliant save out of Brad Friedel.
The home side were showing more attacking enterprise and deserved to take the lead after 31 minutes, but there was a slice of good fortune about the goal.
It seemed a harsh decision when Christopher Samba was pulled up for a foul on Yakubu. Yakubu appeared to win' the free-kick, rather than being the victim of a foul.
England winger Stewart Downing took full advantage by crashing a 25-yard free-kick past Friedel, though the goalkeeper had reason to question a gap in the defensive wall.
The game was played at a tremendous pace with the 25,000 crowd enjoying the standard of entertainment.
Blackburn manager Mark Hughes was spoken to in the dug-out by the referee shortly before half-time. The fourth official had drawn the referee's attention to remarks made by Hughes to a linesman.
Middlesbrough deserved to go in in the lead, but Blackburn soon showed they meant business after the break by piling on pressure for an equaliser.
The game was held up for several minutes while Blackburn striker McCarthy received attention. McCarthy collapsed and there were anxious moments before he was carried off on a stretcher.
Substitute Santa Cruz soon made his presence felt when he sent a powerful header past Mark Schwarzer, following a David Bentley left-wing cross.
Substitute Derbyshire took over from Jason Roberts and immediately won the hearts of the Blackburn fans with a brilliant shot which left Schwarzer helpless.
Middlesbrough fought desperately in the closing stages and were unlucky when a close-range Wheater header was cleared off the line.
At the final whistle players had to be parted. It was not clear why, but it provided a unsatisfactory end to an otherwise sporting game.