The Yellow Submarine are faced with a near-impossible task after falling to a heavy 4-0 defeat in last week's trip to the Stade Velodrome.
Match preview
After experiencing a disastrous result last Thursday, Villarreal have their work cut out if they are to keep their hopes alive of replicating their 2021-22 run to the Europa League trophy.
The Yellow Submarine bounced back from their fruitless trip to France to claim all three points in Sunday's five-goal thriller with Real Betis.
Villarreal came from behind on a couple of occasions thanks to an Alex Baena effort and a Sokratis Papastathopoulos own goal, before Alexander Sorloth scored his 13th league goal of the season to guide his team to a third consecutive La Liga victory.
Marcelino's charges will now return home for the first time since thrashing Granada 5-1 earlier this month, and they will be looking for a repeat of that free-scoring display on Thursday.
Although they may struggle to overturn the four-goal deficit, Villarreal will at least fancy their chances of claiming a second-leg victory, having won nine of their last 10 home matches in the Europa League (D1) since losing to Valencia in April 2019.
Marseille may have begun the campaign under Villarreal boss Marcelino, but they are currently under the watch of their third coach of the season after Jean-Louis Gasset replaced Gennaro Gattuso last month.
Gasset has kicked off his tenure with five consecutive victories, including the dominant performance in the first leg to leave Marseille on the verge of sealing their place in Friday's quarter-final draw.
A Jordan Veretout effort and a Yerson Mosquera own goal gave Marseille a two-goal lead inside the opening half-hour against Villarreal, before Pierre-Emerick Aubameyang netted a brace to seal a 4-0 victory.
Aubameyang went on to score two more goals in Sunday's 2-0 win over Nantes, ensuring they are yet to lose a home game inside regulation time this season.
Marseille will now turn their focus back to European action, and they will certainly be confident about protecting their sizeable first-leg advantage, having conceded four or more goals in just one competitive game this season.
Villarreal Europa League form:
W
W
W
D
W
L
Villarreal form (all competitions):
D
D
W
W
L
W
Marseille Europa League form:
W
W
L
D
W
W
Marseille form (all competitions):
L
W
W
W
W
W
Team News
Villarreal are still having to cope without the services of Raul Albiol, Alfonso Pedraza, Ramon Terrats and Denis Suarez.
Juan Foyth is closing in on a return to fitness, but the defender is unlikely to return in time for Thursday's second leg.
Left-back Alberto Moreno will miss out through suspension after last week's substitute appearance was cut short by a red card.
As for the French side, they are still unable to call upon the injured quartet of Samuel Gigot, Amir Murillo, Bilal Nadir and Valentin Rongier.
Gasset will be hoping to have Jonathan Clauss back for the trip to Spain after the right-back sat out the win over Nantes due to a slight knee problem.
Aubameyang will be looking to continue his impressive run of form, having scored eight goals across Marseille's last five competitive matches.
Villarreal possible starting lineup:
Reina; Femenia, Mandi, Bailly, Cuena; Akhomach, Parejo, Coquelin, Baena; G Moreno, Sorloth
Marseille possible starting lineup:
Lopez; Clauss, Mbemba, Balerdi, Merlin; Veretout, Kondogbia, Harit; Sarr, Ndiaye, Aubameyang