The Serie A powerhouse have chosen former Italian national team boss the veteran manager as their manager for the remainder of the campaign.
Spalletti steps in for Igor Tudor, who was let go post the Lazio setback last weekend.
Tudor had joined the club in March filling the shoes of Thiago Motta but departed after seven months after an eight-game winless streak.
Under Spalletti, Napoli clinched the Serie A championship in 2022-23 then moving on to lead the Italian national team, who had failed to qualify for the 2022 World Cup under former boss Roberto Mancini.
He secured their spot in Euro 2024 where they were knocked out in the last 16 by Switzerland.
However, Spalletti was sacked by Italy 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 behind leaders Napoli after nine games.
In the Champions League, they sit 25th in the league phase, having lost once and drawn twice in their opening three matches.
