The two European powerhouses currently occupy the top two spots in the group and the victor in this tie - if there is one - will take a giant stride towards the knockout stages.
A trip to San Siro to take on an in-form Milan side would normally evoke fear into the hearts of teams, but not Lille, who stormed to a remarkable 3-0 victory to condemn the Serie A leaders to their first defeat of the campaign.
The much-coveted Yusuf Yazici, who has now found himself linked with a move to Arsenal, scored a trio of goals at the home of the Rossoneri - his second hat-trick in the 2020-21 Europa League after the 23-year-old also put three past Sparta Prague on matchday one.
That victory in Milan ended a run of three consecutive draws for Lille, and while Christophe Galtier's men suffered a shock defeat to Brest in the days following their triumph against the Rossoneri, Les Dogues trounced Lorient 4-0 on their return from the international break.
Yazici once again earned plenty of plaudits with another two goals to his name in Lille colours, but perhaps the biggest success story of the day was Jonathan David finally breaking his duck and scoring his first goal for Les Dogues at the 14th attempt.
As the only side in Group H yet to taste defeat, another victory over Milan would see Galtier's men put one foot firmly in the knockout stages, but Milan will be out for blood when they make the journey to the Stade Pierre-Mauroy.
Milan welcomed Lille to their home having won 10 of their opening 11 matches of the 2020-21 campaign, and not even Dogues supporters could have foreseen their side hit the Rossoneri for three without reply - which was Milan's heaviest-ever European defeat at San Siro.
Stefano Pioli will no doubt consider that lowly defeat as just a temporary blip, with Milan still unbeaten in the Italian top flight, and the Rossoneri displayed their title credentials with a 3-1 victory over Napoli last time out.
In a turn of events that surprised no-one, Zlatan Ibrahimovic got on the scoresheet once again for Milan and took his tally to 10 league goals for the season with a brace on Sunday, while Jens Petter Hauge got off the mark for the season with third for the Rossoneri in the dying embers.
Ibrahimovic did not enjoy the best of outings against Lille, though, as he was hauled off on the hour mark as Yazici dominated the San Siro turf, and the veteran Swede will not be able to stamp his authority on Les Dogues's ground after suffering an injury in the win over Napoli.
Milan marched to comfortable victories over Celtic and Sparta Prague before that loss to Lille, and Pioli's men should still feel confident of making the knockout stages no matter how many points they can accrue this week.
Lille Europa League form: WDW
Lille form (all competitions): DDDWLW
AC Milan Europa League form: WWWWWL
AC Milan form (all competitions): DWWLDW
Lille will be able to welcome back the trio of Reinildo, Jose Fonte and Burak Yilmaz - who were all suspended for the win over Lorient - but the latter is not expected to start up top ahead of Yazici or David.
As mentioned, the visitors will have to make do without Ibrahimovic due to the thigh problem he sustained against Napoli, which could prove to be a real blow in Milan's bid to keep their strong results going over the next few weeks.
Samu Castillejo, Brahim Diaz and Diogo Dalot are some of the names likely to feature on Pioli's teamsheet this week, but Hauge's first goal for the club is unlikely to be enough for him to start this encounter.
Lille possible starting lineup:
Maignan; Pied, Fonte, Botman, Bradaric; Ikone, Andre, Soumare, Bamba; David, Yazici
AC Milan possible starting lineup:
Donnarumma; Dalot, Kjaer, Romagnoli, Hernandez; Tonali, Kessie; Castillejo, Diaz, Krunic; Rebic
We say: Lille 2-1 AC Milan
The loss of Ibrahimovic is a crushing blow to a Milan side seeking revenge against a talented Lille outfit, and Galtier's men know that they can beat the in-form Rossoneri having done so convincingly already. We are expecting a much tighter affair here than we saw at San Siro, but Lille should do enough to get over the line and take another step towards the knockout stages.