The Serie A powerhouse have named former Italy boss the veteran manager to take the helm until the end of the season.
The 66-year-old takes over from Igor Tudor, who was sacked after the Serie A side's defeat by Lazio on Sunday.
The former boss came on board 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 before taking charge of Italy, who had failed to qualify for the 2022 World Cup with Mancini at the helm.
Under his guidance, they made it to Euro 2024 exiting in the last 16 stage against 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.
He has previously coached Inter Milan, Roma, and Udinese in Italy's top flight and secured two Russian Premier League titles with Zenit St Petersburg.
Massimo Brambilla took interim charge of Juventus in the midweek 3-1 triumph over Udinese which left them seventh in Serie A - six points behind leaders Napoli after nine games.
They are 25th in the league phase of the Champions League, having lost once and drawn twice in their opening three matches.
