The hosts could only take a point from their clash with Strasbourg in a 1-1 draw at the weekend, while Marseille played out a stalemate in the Choc des Olympiques with Lyon by the same scoreline.
A disappointing Europa League exit was clearly still playing on Lille's minds against a relegation-threatened Strasbourg, who managed to walk away from the Stade Pierre-Mauroy with a share of the spoils in a 1-1 draw on Sunday afternoon.
A thumping finish from Ludovic Ajorque saw the visitors strike first, but Jose Fonte ensured that Lille would not suffer back-to-back defeats for the first time this season as his header restored parity for Les Dogues, who still have plenty of work to do if they are to cement their position at the top of the Ligue 1 table.
The fatigue from Thursday's defeat to Ajax was evident as Lille went three games without a win on home soil across all competitions, and due to their Europa League failings, Christophe Galtier's side have only mustered one victory from their last five domestically and continentally.
However, Lyon could not capitalise on Lille's failure to win at the weekend, so Galtier's men remain in first place, but Paris Saint-Germain took advantage by thrashing Dijon to move two points behind Les Dogues, who will inevitably start looking over their shoulder now.
Despite their shaky form over the past couple of weeks, Galtier's side - who can now fully focus on their title charge after being knocked out of Europe - will be aiming to extend their unbeaten league run to 10 matches this weekend, although they have won just two of their last six Ligue 1 home matches and Marseille will be buoyed by the arrival of their new leader.
Jorge Sampaoli must have been watching on with admiration as Marseille deservedly claimed a point from their meeting with title hopefuls Lyon last time out, with Arkadiusz Milik returning to the starting lineup with a bang as his penalty cancelled out Karl Toko Ekambi's opener on the night.
Nasser Larguet has helped steady the ship since Andre Villas-Boas's dramatic departure, but the 62-year-old is now set to make way for former Argentina boss Sampaoli, and Marseille fans will be hoping that the iconic 60-year-old can take a leaf out of Marcelo Bielsa's book at the Orange Velodrome.
Due to quarantine regulations amid the coronavirus pandemic, Sampaoli is not expected to be on the touchline for Wednesday's game, where Marseille will somehow attempt to stretch their unbeaten run across all competitions to six matches, although they are yet to win away from home in Ligue 1 since the turn of the year.
The seventh-placed Olympiens are still realistic contenders for the final European spot as they sit two points behind fifth-placed Metz - who have played a game more - so if results go their way this week, Marseille could be back in the top five by the time Sampaoli takes the reins.
Lille's Luiz Araujo and Marseille's Valere Germain both found the back of the net in a 1-1 draw earlier in the campaign, but Les Dogues have only won one of their last six against Wednesday's opponents on their own turf - a 3-0 triumph in the 2018-19 campaign.
Lille Ligue 1 form: WWWDWD
Lille form (all competitions): WDLWLD
Marseille Ligue 1 form: DLDWDD
Marseille form (all competitions): LWDWDD
Lille right-back Zeki Celik shook off a minor injury to make the bench against Strasbourg, but his compatriot Burak Yilmaz is yet to recover from a calf problem, and captain Fonte has admitted that the league leaders are missing the inspirational Turkish forward.
Celik could make an immediate return at right-back for Jeremy Pied, and Lille have no other injury or suspension concerns for this game, but it would be a surprise to see Galtier not rotate as he looks to get his side up and running again.
Leonardo Balerdi should fill the void left by Gonzalez's absence in the heart of defence, but Benedetto is not likely to displace Milik up top.
Lille possible starting lineup:
Maignan; Celik, Fonte, Botman, Bradaric; Ikone, Andre, Xeka, Bamba; David, Yazici
Marseille possible starting lineup:
Mandanda; Lirola, Caleta-Car, Balerdi, Nagatomo; Kamara, Rongier; Thauvin, Payet, Henrique; Milik
We say: Lille 1-0 Marseille
Larguet will be determined to go out with a bang before he passes the torch over to Sampaoli, but Marseille are fighting an uphill battle to upset the league leaders this weekend. Galtier should be demanding an immediate response from his team after a minor setback, and even though Marseille have looked more resolute in recent weeks, their away form is highly concerning and Lille should avoid being usurped at the top with a narrow win on Wednesday.