Dries Mertens, Jose Maria Callejon and Amin Younes all found the back of the net to put Gennaro Gattuso's side on 45 points from 28 games, three points adrift of fifth-placed AS Roma who lost 2-0 at AC Milan earlier on Sunday.
SPAL equalised in the first half through Andrea Petagna but they could not sustain the pace at the San Paolo.
They are now bottom of the table on 18 points, eight points from the safety zone with 10 games left.
Petagna made it 1-1 in the 29th minute by beating keeper Alex Meret with a low shot, SPAL's first attempt of the game, only for Napoli to regain the advantage through Callejon after he was set up by Eljif Elmas.
The hosts had a third goal disallowed after VAR ruled that Mertens was offside when he crossed for Lorenzo Insigne on the stroke of halftime.
Younes put the result beyond doubt when he headed the ball home from Ruiz's perfect cross in the 78th minute.
SPAL next host Milan while Napoli, already guaranteed a place in the Europa League thanks to their Coppa Italia triumph, travel to in-form Atalanta, who are fourth on 57 points and occupy the last Champions League qualifying spot.