The visitors scored first on a strike in the 20th minute by Alberto Paloschi, but Sampdoria'S Karol Linetty replied for the hosts just five minutes later with an assist from Fabio Quagliarella.
Sampdoria were much the better side in the second half and pulled ahead in the 60th minute with Gregoire Defrel's goal.
Quagliarella also assisted on the second goal.
For Spal, it was a third consecutive loss.
The victory lifts Sampdoria to 11 points from seven matches, good enough for 8th place. They trail cross-town rivals Genova by a point, though the second club have a game in hand.
Spal, with 9 points from seven, are 13th in Serie A.
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