Pioli has the toughest of assignments in what will be a cauldron atmosphere at the San Siro stadium.
Chinese-owned Inter wielded the axe when they sacked Frank de Boer after just 11 games, and Pioli has the toughest of assignments in what will be a cauldron atmosphere at the San Siro stadium.
The ex-Lazio boss looks set to revamp Inter's line-up for what he has called a "crucial" game as they bid to rise from their current ninth position in Serie A, 13 points off leaders Juventus.
"It's a crucial game for us. Milan are doing well, but we'll go into it with confidence," Pioli said.
One option for Pioli is to deploy a 4-3-3 with Argentine striker Mauro Icardi, who has hit a league-tying 10 goals in 12 appearances, flanked by Antonio Candreva and Argentina's Ever Banega.
"It will be a crucial match for us, because we need to win it," said Inter's Joao Mario, who helped Portugal beat France in July's Euro 2016 final.
"Obviously, I can't compare it to the final we played against France at Euro 2016, but in a sense it's like a major tournament final -- and we want to win it for the fans."
Meanwhile AC Milan will hope to brush aside Carlos Bacca's goal drought and defender Alessandro Romagnoli's injury and keep up their title charge.
The seven-time European champions are finally back in contention after years of mediocrity, although Colombia striker Bacca has failed to score in their last five league outings and Romagnoli's absence is a key concern.
Yet the setbacks have not stopped Vincenzo Montella's youthful Rossoneri side giving leaders Juventus a run for their money.
Milan's purple patch, which includes one defeat in their last nine games, has left them just five points off the top in a run which has won plaudits.
"Milan are doing much better than they have been, they have a lot of young players who understand how to play football and as a result the games are great to watch," former Milan midfielder Ruud Gullit told Gazzetta dello Sport.
Milan's hopes of securing a place in European competition next season were boosted by a 1-0 home win over Juventus at the San Siro last month.
And midfielder Andrea Poli told Milan Channel: "We've really been working hard these past few days, the derby is very important to us, and our fans.
"It's another big test for us after beating Juventus, but Inter haven't been doing great lately and they will be determined to get back on the right track.
"We'll keep our feet on the ground, but we have to be conscious we're doing really well."
Roma, in second place, travel to Atalanta without veteran playmaker Francesco Totti, who was set to start from the bench before suffering a knock to his hip.
Mohamed Salah's maiden league hat-trick in a 3-0 win over Bologna a fortnight ago ensures the Egyptian will line up alongside Radja Nainggolan and Diego Perotti in Roma's midfield.
It leaves Bosnia international Edin Dzeko as the lone striker, but in prime position to add to the league-leading goal tally he shares with Icardi.
Elsewhere, fourth-placed Lazio host Genoa hoping to close the gap on Milan, while sixth-placed Napoli travel to Udinese with one eye on Wednesday's Champions League clash at home to Dinamo Kiev.
Juventus are in a similar position, and coach Massimiliano Allegri will be forced to dig deep into his injury-depleted squad ahead of Saturday's home game with struggling Pescara to keep legs fresh for Tuesday's trip to Sevilla.
Chievo v Cagliari (1400 GMT), Udinese v Napoli (1700 GMT), Juventus v Pescara (1945 GMT)
Sampdoria v Sassuolo (1130 GMT), Atalanta v Roma (1400 GMT), Bologna v Palermo (1400 GMT), Crotone v Torino (1400 GMT), Empoli v Fiorentina (1400 GMT), Lazio v Genoa (1400 GMT), AC Milan v Inter Milan (1945 GMT)