The Azzurri enjoy a four-point lead over Massimiliano Allegri's men so victory at San Siro would see the southern club move seven points clear while keeping pace with leaders Juventus.
The Italian champions must wait until Monday night to face Lazio, meaning Mazzarri's side could keep the race for the Scudetto alive by closing the gap to six points with victory on Sunday.
Mazzarri told sscnapoli.it: "This kind of match is unique and from a psychological point of view.
"AC Milan have made a great comeback so we know this is going to be tough. We will have to be brilliant and determined.
"Let's focus on these last few matches to consolidate our extraordinary season.
"We have more 14 points than we had last year and we want to qualify for the Champions League again. That would be an extremely impressive achievement."
Milan must cope without star striker Mario Balotelli, who starts a three-match ban after verbally abusing a referee during last week's draw at Fiorentina. The Italy international will also miss high-profile clashes against Juventus and Catania.
La Viola, meanwhile, are six points behind Milan and looking to narrow that gap with a positive result against Atalanta on Saturday night.
The Bergamo outfit stunned Inter Milan with a 4-3 victory at San Siro last time out and Andrea Stramaccioni must get the Nerazzurri back on track against Cagliari, who have been given permission to use the Stadio Nereo Rocco in Trieste.
The second Derby della Lanterna takes place this weekend with Genoa eager to avenge November's 3-1 defeat to newly-promoted Sampdoria with a reversed outcome at the Marassi.
While Samp are safe in mid-table, Genoa are struggling to break free of a three-way tie for 19th place with Siena and Palermo, who are showing signs of recovery at the right time.
The Sicilians claimed back-to-back victories for the first time this season in beating Samp 3-1 while Siena held resurgent Parma to a goalless draw in Tuscany.
Palermo host 12th-placed Bologna while Siena visit bottom side Pescara, who are six points adrift of safety and preparing for life in Serie B.
Elsewhere, Catania are looking to beat their all-time points record in the top flight by reaching 49 should they win at Chievo's Stadio Marc'Antonio Bentegodi.
Parma take on Udinese and Torino host Roma in the weekend's remaining matches before Lazio welcome Juventus to the capital on Monday night.
The Biancocelesti could capitalise on any slip-up from Fiorentina to go fourth with victory over Juve, who are now out of the Champions League following a 4-0 aggregate defeat to Bayern Munich.