The Serie A powerhouse have named ex- Italy boss the veteran manager to lead the team for the rest of the term.
The experienced coach steps in for Igor Tudor, who was let go post the Lazio setback last weekend.
Tudor had joined the club in March to replace Thiago Motta but exited following a seven-month stint at the end of an eight-match winless run.
Spalletti guided Napoli to the Serie A crown in 2022-23 then moving on to lead the Italian national team, who had failed to qualify for the 2022 World Cup with Mancini at the helm.
He secured their spot in Euro 2024 but were eliminated in the round of 16 by Switzerland.
Yet, the Italian FA let Spalletti go in June following a loss to Norway in World Cup qualifying, as Italy faced the possibility of not making a third World Cup in a row.
Spalletti's managerial career includes Inter Milan, Roma, and Udinese in Serie A and won the Russian Premier League twice with Zenit St Petersburg.
Massimo Brambilla served as interim manager for Juventus for their 3-1 win against Udinese on Wednesday which left them seventh in Serie A - six points adrift of Napoli at the top after nine rounds.
They are 25th in the league phase of the Champions League, after recording one defeat and two ties in the initial three fixtures.
