The Old Lady have named former Azzurri manager 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 last weekend.
Tudor arrived at the club in March as Thiago Motta's replacement but left after seven months at the end of an eight-match winless run.
Spalletti guided Napoli to the Serie A crown in 2022-23 prior to assuming the Italy role, after the team's failure to reach 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.
However, Spalletti was sacked by Italy in June after a World Cup qualifying defeat by Norway, 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 during the 3-1 victory over Udinese on Wednesday moving them to seventh position in the league - six points behind leaders Napoli after nine games.
In the Champions League, they sit 25th in the league phase, after recording one defeat and two ties in the initial three fixtures.
