The former Liverpool forward had been on the field just six minutes when he curled a left-footed shot into the top corner to break the deadlock with his first goal of the season.
It was only Milan's fourth win of the campaign but lifted them into 10th on 13 points.
Sergio Floccari wasted SPAL's best chance by missing the target with a header six yards out.
Suso replaced Castillejo in the 57th minute and scored with Milan's first real chance of the second half after Krzysztof Piatek was fouled.
Piatek and Paqueta both had chances to extend the lead but Suso's goal proved enough to inflict a fifth successive away defeat on second-bottom SPAL.