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 the Nerazzurri above their city rivals in the table.
The former Galatasaray boss won three Scudetti and two Coppa Italia titles in his four-your spell at Appiano Gentile between 2004 and 2008 but he returns to a club struggling to live up to past glories.
A fifth-place finish last season left them without Champions League football to enjoy this term and their current domestic form has been underwhelming, with Inter languishing in mid-table, 12 points adrift of leaders Juventus.
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 always sure to appease the Nerazzurri's restless fans is a derby victory - especially in this instance, as it would mean overtaking neighbours Milan in the standings.
Just one point separates the two sides heading into Filippo Inzaghi's first 'Derby della Madonnina' as Rossoneri 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 the Rossoneri'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.
In terms of injury news, Milan midfielder Nigel de Jong withdrew from the Netherlands squad with a hamstring problem during the recent international break and will undergo a late fitness test.