Simone Inzaghi's side bounced back from a home defeat to Inter Milan to move ahead of AC Milan, who play in Udinese later Sunday.
Immobile scored after 26 and 35 minute to bring his tally to eight league goals this season with Danilo Cataldi (59) and Marco Parolo (70) adding two more in the second half.
Lazio with 21 points from 11 games are ten points behind leaders Juventus, who continued their unbeaten run with a 3-1 win over Cagliari on Saturday.
Italian international Immobile volleyed in the first after 26 minutes off a Cataldi corner, past SPAL goalkeeper Vanja Milinkovic-Savic, brother of Lazio midfielder Sergej, who was also playing at the Stadio Olimpico.
But the celebrations were short lived with Mirco Antenucci tapping in the equaliser for SPAL two minutes later.
Vanja Milinkovic-Savic denied Immobile from close range and Sergej Milinkovic-Savic sent over before Immobile's second.
Felipe Caicedo broke through the SPAL defence and set up Immobile, whose shot took a deflection off Filippo Costa over the SPAL goalkeeper.
Blunders by SPAL's Brazilian defender Everton Luiz allowed Cataldi and Parolo to break through in the second half, but Immobile was denied a hat-trick by the woodwork.
SPAL, a club from Ferrara in Emilia-Romagna, stay 15th after their seventh defeat of the season.
Lazio next host French club Marseille at the Stadio Olimpico in the Europa League on November 8, before travelling to Sassuolo in Serie A.