The Old Lady have chosen ex- Italy boss the veteran manager as their manager for the remainder of the campaign.
The experienced coach steps in for Igor Tudor, who was dismissed post the Lazio setback on Sunday.
The former boss came on board in March to replace Thiago Motta but left after seven months at the end of an eight-match winless run.
Under Spalletti, Napoli clinched the Serie A championship in 2022-23 before taking charge of Italy, which missed out on the 2022 World Cup under former boss Roberto Mancini.
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, 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 adrift of Napoli at the top after nine rounds.
Their Champions League campaign sees them in 25th place in the group stage, having lost once and drawn twice in their opening three matches.
