Having been announced as Walter Mazzarri's replacement last week, Mancini's first task is to mastermind a triumph at San Siro that would take Inter above their bitter rivals in the Italian top flight.
Mancini won three league titles and two Coppa Italia crowns in his four-your spell at at the Inter helm, which ended in 2008, but he returns to a club struggling to live up to past glories.
A fifth-place finish last season left them without UEFA Champions League football this term and domestic form has been underwhelming, with Inter languishing in mid-table.
Leaders Juventus are 12 points clear of Inter, who ended the last decade with five consecutive Scudetto triumphs - three of those under Mancini.
Inter president Erick Thohir has warned that expectations remain high, with Mancini expected to deliver European qualification.
The Indonesian described the Europa League - which the club are in this season - as a "minimum goal", but the main aim is a return to the Champions League.
One thing sure to appease the club's restless fans is a derby victory, especially knowing that it would mean Inter would overtake their neighbours in the standings.
Just one point separates the two sides heading into Filippo Inzaghi's first Milan derby as a coach - and the 41-year-old needs a response from his side following a four-game winless run in the league.
Milan were held to a 2-2 draw at Sampdoria before the international break, with Daniele Bonera's late red card ensuring he will miss this weekend's game.
Indeed, draws have been a regular feature of Milan's season, with five from their first 11 matches keeping Inzaghi's men in seventh, despite having lost just twice.
Both meetings went the way of the designated hosts last season, with a solitary goal enough to settle matters on each occasion.
But winning the derby is not always a positive omen. After Inter prevailed in December, they went on a six-game winless run, while Milan responded to the defeat by winning four of the next six in all competitions.
Milan midfielder Nigel de Jong withdrew from the Netherlands squad with a hamstring injury in the recent international break and will undergo a late fitness test.
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