The Serie A powerhouse have named previous Italian national team manager the veteran manager to lead the team for the remainder of the campaign.
Spalletti steps in for Igor Tudor, who was sacked following the loss to Lazio on Sunday.
Tudor arrived at the club in March filling the shoes of Thiago Motta but left after seven months following a string of eight matches without a victory.
Under Spalletti, Napoli clinched the Serie A championship in 2022-23 before taking charge of Italy, after the team's failure to reach the 2022 World Cup during Roberto Mancini's tenure.
He helped them qualify for Euro 2024 where they were knocked out in the last 16 by Switzerland.
Nonetheless, Italy dismissed Spalletti in June following a loss to Norway in World Cup qualifying, with the Azzurri at risk of missing out on a third consecutive World Cup.
Spalletti's managerial career includes Inter Milan, Roma, and Udinese in Serie A and secured two Russian Premier League titles 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.
Their Champions League campaign sees them in 25th place in the group stage, with one loss and two draws in their first three games.
