The Paraguay international was drafted into the starting line-up in place of Benni McCarthy, who suffered concussion after taking a blow to the head in last weekend's Premier League victory over Middlesbrough.
The former Bayern Munich striker had opened his Blackburn account after replacing McCarthy an hour into the Boro clash and he wasted little time in doubling his tally after capitalising on good work from strike partner Jason Roberts.
Roberts turned marker Heikki Pulkinnen and fed Santa Cruz who powered into the box and found the far corner of the net with a piercing low left-foot shot.
In a low-tempo game, Rovers bossed the majority of possession with David Bentley often the architect of their most promising moments.
On 36 minutes the England hopeful tested Janne Korhonen with a powerful shot from the edge of the box which was straight at the goalkeeper.
Then on the stroke of half-time, David Dunn tried his luck with a shot that flashed marginally wide of the far post.
MyPa offered more of an attacking threat at the start of the second period as Rovers took their foot off the gas.
Eero Peltonen was left unmarked in the 55th minute and latched onto a flick on into the box, but Christopher Samba recovered as the striker was about to pull the trigger and nudged the ball out of play.
At the other end, Tuomas Kansikas almost scored a comical own goal when his horribly sliced a clearance looped just wide of the mark with the keeper flat-footed.
Hughes sent on Matt Derbyshire, Brett Emerton and Tugay in the second period in an effort to sew up the tie.
Santa Cruz couldn't direct a towering 72nd minute header on target, while Emerton's first touch almost resulted in the Australian international squeezing a low shot under the keeper from close range after good work from Tugay.
But, despite dominating the match, Rovers failed to find a second away goal that would have killed off the spirited home side ahead of the return leg.