Mancini - who replaced Walter Mazzarri at the helm of the Italian giants last week - is not afforded time to settle into the top job.
Instead, a meeting with their city rivals and a clash with Roma are up first domestically for Mancini, who led the club to three successive titles and two Coppa Italia successes in a four-year tenure that ended in 2008.
Milan midfielder Sulley Muntari knows just how much the match means for players and supporters, having played for both sides, and believes victory at San Siro could kick-start his current employers' season.
"The derby means so much for us, for the table, but also for our self-confidence," Muntari told Milan Channel.
"We must give our all for our fans. It is going to be a very important match and we'll do everything to win.
"This is a unique event and therefore means a huge amount in the city.
"We've certainly been very focused and concentrated on the game. We've got to run and fight to the end, not think of what could go wrong.
"Mancini is a great coach who has done well everywhere. He will have an influence - but he won't be the one playing on the pitch."
Mancini, who said he considered the club his "home" when returning last week, will be banking on the goals of Mauro Icardi.
Massimiliano Allegri's men have bounced back from defeat at Genoa in impressive fashion and their 7-0 trouncing of Parma last time out was emphatic.
Napoli and Sampdoria - third and fourth - will be big favourites to defeat Cagliari and Cesena respectively, while Genoa's improvement will be tested when Palermo come to town.
