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.
The 49-year-old has since managed Manchester City and Galatasaray and takes over an Inter side languishing in ninth - 12 points adrift of leaders Juventus after just 11 matches.
Inter have won just four Serie A games this term and trail the seventh-placed Milan by a point.
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.
The Argentina international has scored seven times in Serie A - just two players have netted more this season.
Juve face a test of their credentials when they go to Rome to face fifth-placed Lazio on Saturday.
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.
But Lazio have won four of their five home fixtures this season and will be no pushover.
Roma, who sit three points adrift of the leaders in second, are also in action on Saturday, when they go to struggling Atalanta.
The 17th-placed side have moved out of the relegation zone after losing just one of their last five, but have scored a league-low four goals.
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.
Genoa are undefeated in six matches.
Verona have not won in five and host out-of-sorts Fiorentina, while Parma and Chievo, both trapped in the bottom three, battle Empoli and Udinese respectively.
And Sassuolo will be out to extend their five-match unbeaten run when they visit Torino.
