The Old Lady have appointed ex- Azzurri manager the veteran manager to take the helm until the end of the season.
The experienced coach steps in for Igor Tudor, who was sacked post the Lazio setback recently.
Tudor arrived at the club in March to replace Thiago Motta but departed after seven months after an eight-game winless streak.
Spalletti guided Napoli to the Serie A crown in 2022-23 prior to assuming the Italy role, which missed out on the 2022 World Cup with Mancini at the helm.
He secured their spot in Euro 2024 exiting in the last 16 stage against Switzerland.
Nonetheless, Italy dismissed Spalletti in June after a World Cup qualifying defeat by Norway, putting Italy in danger of missing a third straight World Cup.
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 moving them to seventh position in the league - trailing leaders Napoli by six points after nine matches.
In the Champions League, they sit 25th in the league phase, with one loss and two draws in their first three games.
