The former fan favourite will be hoping his first competitive game in charge ends in a morale-boosting win, but the Biancocelesti have provided their new coach with a strong squad
Both clubs appointed new coaches in June following disappointing campaigns last term - Milan finished eighth, a point and a place above Lazio, after a season that saw Clarence Seedorf replace Massimiliano Allegri at the helm in January.
The Dutchman has since been succeeded by another Milan great in the form of Inzaghi and the ex-Italy international will be tasked with returning the Serie A giants to happier times, specifically European competition.
Seven league wins from nine at the end of last season were not enough to lift Milan into the Europa League and there have been plenty of comings and goings at San Siro during the transfer window.
Robinho and Mario Balotelli have both moved on, with Inzaghi able to bring in the likes of Alex, Jeremy Menez and - most recently - Fernando Torres on a two-year loan deal, although the latter only agreed terms on Friday meaning it would be a shock if he played.
Lazio also saw two coaches take charge last season, with Edoardo Reja replacing Vladimir Petkovic in January before former Bologna coach Pioli was appointed in June.
Stefan de Vrij, Filip Djordjevic, Dusan Basta and Marco Parolo have all been recruited over the close-season, with Pioli also seeking to re-establish his club in European competition.
Inazghi must make do without Nigel de Jong (groin) and long-term absentee Riccardo Montolivo (broken leg), while Lazio goalkeeper Federico Marchetti is suffering from a pulled thigh muscle.