Massimo Maccarone scored the equalizer as Empoli earned a 1-1 Serie A draw at Milan on Sunday.
Destro arrived on loan from Roma during the transfer window, making his debut in a 3-1 victory over Parma a fortnight ago.
The striker failed to find the target on that occasion, but hooked home from a Giacomo Bonaventura cross in the 40th minute to hand Milan the advantage.
The goal came against the run of play during a half in which Empoli caused the home team all manner of problems - Mario Rui narrowly missing the target with an audacious effort from the halfway line.
However, Massimo Maccarone popped up in the 68th minute to earn his side a well-deserved point and leave Milan with just one win from its last six fixtures in all competitions.
Goalkeeper Diego Lopez was sent off in the closing stages after being judged to have handled a Francesco Tavano shot just outside the area, but Empoli was unable to capitalize on the man advantage.
Destro returned from suspension to lead the Milan line, but it was Empoli who applied the early pressure - Manuel Pucciarelli hammering a shot into the side-netting while a frustrated Maccarone waited in a more central position for a pass that never came.
Milan coach Filippo Inzaghi looked concerned within 10 minutes of the match kicking off, and Rui's speculative strike from the halfway line almost left the home side red-faced when it drifted agonizingly wide of the left-hand post, much to the relief of backtracking Lopez.
Milan had been forced to take off Alex due to a facial injury picked up in a tackle just prior to Rui's long-range effort, but did begin to settle as the first half progressed.
That said, Luigi Sepe had precious little to occupy his time in the Empoli goal, but looked less than convincing when dealing with an Andrea Poli cross-come-shot after 27 minutes.
Lopez then produced a good save to keep out Rui, before Destro netted his first Milan goal five minutes from the break.
The striker latched onto a low Bonaventura cross to divert the ball beyond Sepe from close range, although there were some suspicions of offside.
Daniele Croce failed to get enough purchase on his attempt at an equalizer on the hour as the ball bobbled nicely into the arms of Lopez, and Rui blasted over a free kick from a promising position.
But Empoli got a hard-earned equalizer when Maccarone guided a header just inside the left-hand post from a superb Elseid Hysaj cross from the right.
Tavano's shot was tipped over by the onrushing Lopez seven minutes from time, but the keeper was given his marching orders with the touch deemed to have happened outside the box.
Luckily for Milan, the club had not used its full allocation of substitutes and was able to bring Christian Abbiati off the bench in place of Destro, although the home side was left to cling on for a precious point.