The first leg this week will take place at the Stade Velodrome, with Marseille's new boss Jean-Louis Gasset looking to continue his excellent start in charge.
Match preview
Since Gennaro Gattuso became the third Marseille boss to leave the post since June, fortunes have improved drastically on the pitch.
A 1-0 defeat at Brest was the final straw for the Italian, and he was replaced by Gasset, who had recently been sacked midway through the Africa Cup of Nations by Ivory Coast.
While plenty of eyebrows were raised at his appointment, Gasset has made his critics eat their words early into his reign, as Marseille have been irresistible since he came in.
Three wins from three to start began with their second-leg victory over Shakhtar Donetsk in the previous round of this competition, progressing thanks to a 3-1 win here at the Velodrome.
Gasset's two Ligue 1 games in charge have produced very convincing Marseille wins too, as Montpellier were beaten 4-1 here, before they went to Clermont and thrashed them 5-1 on the road on Saturday.
That has moved OM back into European contention after they had slipped towards the bottom half under Gattuso, with just five points separating them from Lille in fourth.
Focus will turn back to Europe now though, as Marseille chase a first-ever Europa League crown.
Despite being 1993 Champions League winners, OM have never been able to get over the line in this competition, losing three finals, including most recently against Atletico Madrid in 2018, which was funnily enough their last meeting with a Spanish club.
Fellow Spaniards Villarreal will look to end Marseille's European campaign early here, in what is just the second knockout stage appearance for the French club in six seasons.
The 2021 Europa League champions may have more recent pedigree in Europe, with four semi-finals in under two decades in addition to that success three years ago, but there are doubts as to whether they can do it on the continent without Unai Emery leading the side.
Shortly after Emery departed for Aston Villa last season, Villarreal were knocked out of the Europa Conference League by Anderlecht at this stage.
European qualification has not been on the agenda for the Yellow Submarine domestically this season either, as a seven-game unbeaten run has been required to put distance between themselves and the bottom three.
Back-to-back wins against Real Sociedad and Granada have well and truly put those fears to bed, scoring eight goals in the process, while also recording a 5-3 win at Barcelona just over a month ago.
Their underwhelming league performance throughout the season does mean that their only likely route back into Europe next season is if they can win this competition though.
Marseille Europa League form:
W
W
W
L
D
W
Marseille form (all competitions):
D
D
L
W
W
W
Villarreal Europa League form:
L
W
W
W
D
W
Villarreal form (all competitions):
W
D
D
D
W
W
Team News
Pierre-Emerick Aubameyang is set to lead the line for Marseille fresh from going clear at the top in the all-time UEFA Cup/Europa League goalscorer charts, as his strike against Shakhtar moved him above Radamel Falcao with 31.
The playmaking exploits of Amine Harit has been important in Aubameyang racking up that tally this season, as the Moroccan has created the most open-play chances (17), and has the most open-play assists (five) of any player in the Europa League this season.
On the injury front, midfielders Jordan Veretout (back) and Valentin Rongier (knee) are both set to miss out, while central defender Samuel Gigot is struggling with a shoulder issue.
Illness has struck the Villarreal squad ahead of this clash, with Eric Bailly, Santi Comesana and Aissa Mandi among the players said to be struggling with a virus at present.
Goalkeeper Filip Jorgensen is also supposedly one of the players suffering, but Pepe Reina has often been the regular choice in cup competitions, so the 41-year-old should start again.
The illnesses add to a rather lengthy injury list for the visitors, as manager Marcelino is also without the likes of Yeremy Pino, Raul Albiol, Juan Foyth and Denis Suarez.
Jorge Cuenca will be available again after he was suspended at the weekend, but Alfonso Pedraza is struggling to be fit in time to feature due to a sprained ankle.
Marseille possible starting lineup:
Pau Lopez; Mbemba, Meite, Balerdi; Clauss, Harit, Kondogbia, Ounahi, Merlin; Moumbagna, Aubameyang
Villarreal possible starting lineup:
Reina; Kiko Femenia, Mosquera, Jorge Cuenca, Alberto Moreno; Akhomach, Parejo, Capoue, Baena; Sorloth, Gerard Moreno
We say: Marseille 2-0 Villarreal
Villarreal won on their last trip to France earlier this season, beating Rennes 3-2, but the form of Marseille undoubtedly makes the hosts favourites in this first leg.