Goals from Paco Alcacer and Fernando Nino in the first leg gave the Spanish outfit a crucial lead coming into this game, while their two away goals could also turn out to be important in deciding the tie.
Villarreal got off to a disappointing start in the first leg, when striker Paco Alcacer had a penalty saved after half an hour, but the Spaniard got his goal soon after, putting the Yellow Submarine ahead after 40 minutes.
Their lead was then doubled when Nino headed in from close range after he was left alone in the box, giving Unai Emery's side some crucial breathing space.
That was the Spanish manager's 54th Europa League win of his career, having already lifted the trophy three times with Sevilla.
The Yellow Submarine cruised through the group stage, topping their group with 16 points after winning all of their games apart from a 1-1 draw with Maccabi Tel Aviv.
However, Emery's men have struggled domestically recently, failing to register a win from their last six La Liga matches.
Their run has seen the Yellow Submarine drop out of the top three, now occupying sixth spot, meaning they may miss out on European football next campaign.
As a result, the Spaniard will be desperate to advance to the round of 16, as securing the Europa League trophy could be their only means of European qualification for next campaign.
The Austrian outfit find themselves in the Europa League knockout stages after they finished third in their Champions League group, having been drawn with Atletico Madrid and Bayern Munich.
They returned to winning ways last time out after the first-leg defeat, beating Rapid Vienna 4-2 at home in a crucial game at the top of the Austrian Bundesliga.
A Patson Daka hat-trick, followed by a late Karim Adeyemi goal, sealed a sixth consecutive league win for Jesse Marsch's side, moving them six points clear of their opponents at the top of the league.
Die Roten Bullen now look on track for an eighth consecutive top-flight trophy, however Marsch will still be disappointed in their European form, as they fight an uphill battle in the second leg.
Villarreal Europa League form: WWDWWW
Villarreal form (all competitions): DLDLWD
Red Bull Salzburg Europa League form: L
Red Bull Salzburg form (all competitions): WWWWLW
Villarreal remain without midfielder Francis Coquelin, who continues his spell on the sidelines with an ankle injury.
He is joined by fellow midfielder Vicente Iborra, who is yet to feature since the turn of the year with a ligament rupture.
Their injury worries are not limited to midfield either, with experienced right-back Mario Gaspar out for this second leg.
However, they were recently boosted by the return of attacker Samu Chukwueze, who came off the bench in the draw with Athletic Bilbao.
Centre-back Andre Ramalho will be available for Salzburg after he missed the first leg through suspension.
Patson Daka will lead the Salzburg line, having recorded 16 goals and five assists in 14 league games this season, including a hat-trick last time out.
Villarreal possible starting lineup:
Rulli; Foyth, Albiol, Torres, Estupinan; Trigueros, Capoue, Parejo, Gomez; Moreno, Alcacer
Red Bull Salzburg possible starting lineup:
Stankovic; Nissen, Ramalho, Vallci, Ulmer; Mwepu, Junuzovic, Bernede; Berisha, Daka, Aaronson
We say: Villarreal 2-1 Red Bull Salzburg
This definitely has the potential to be a very unpredictable affair, as Salzburg look to attack to reduce their deficit, while Emery's side will aim to defend their lead and advance to the round of 16.
The Austrian outfit will definitely set up in an attacking system, and we see them breaking Villarreal down, but we expect the Yellow Submarine to take advantage of Salzburg committing bodies forward, and catch them on the break, coming out of this game with a narrow win and a fairly comfortable aggregate victory.