The hosts have lost successive away games - 3-0 and 3-2 - and will be looking to bounce back against a Rossoneri side still finding their feet under the new coach
Rafael Benitez's men have fallen six points behind second-placed Roma in the Italian top flight, with Fiorentina closing to within three points of third spot.
But the hosts, who have lost just one of their last 21 league matches on home soil, do boast a good record against the Rossoneri, having avoided defeat against them in the last five meetings.
Napoli have also enjoyed good form in the Coppa Italia, although that run was interrupted by a 3-2 defeat at Roma on Thursday, putting their chances in the two-legged semi-final in jeopardy.
Clarence Seedorf was grateful for two last-gasp goals as Milan sealed victory in their last away game - a 2-1 win at Cagliari - although that was just their second Serie A triumph on the road this term.
The former Netherlands international is yet to taste defeat in the league since taking over from the sacked Massimiliano Allegri. Taking seven points from the last nine available has moved Milan into 10th, six points off the European qualification places.
A 2-2 draw at San Paolo last season, sealed by Stephan El Shaarawy's double after going two goals down, sparked an impressive run of just one defeat from 19 games - going a long way to sealing their unlikely qualification for the Champions League.
The hero of that day will be unavailable as El Shaarawy continues to battle a foot injury.
Daniele Bonera is suspended for Seedorf's side, and Kaka is believed to be battling illness, but Benitez could welcome Valon Behrami back to action ahead of schedule after recovering from a foot operation.