The Spanish side will host the Reds at the Estadio El Madrigal on Thursday for the first leg, looking to extend their unbeaten run in this competition to 12 games, while Liverpool manager Jurgen Klopp is yet to win a European match in Spain.
The Yellow Submarine booked their place in the semi-finals with a convincing 6-3 aggregate win over Sparta Prague, but they face a different challenge against Liverpool.
Villarreal will be taking on the new favourites for the crown after Klopp's men knocked out Borussia Dortmund in the quarter-finals in a dramatic comeback triumph.
The Spanish outfit may be seen as slight underdogs, but they are unbeaten in their last 11 European fixtures and have won all of their six home games in the competition.
In addition, Villarreal have scored in 30 of their last 31 games in the Europa League, and in the second leg of their quarter-final tie against Sparta, the team managed to net four, three of which were scored inside six minutes.
Since their triumph in the Czech Republic, though, they have experienced some unfavourable results in La Liga. They managed to draw level against Rayo Vallecano, but eventually lost 2-1.
Despite heading into this game on the back of two defeats and a draw, Villarreal will take comfort from their home form in the Europa League, particularly as they have conceded just one goal in the six games that they have hosted.
Recent form: WDWDWW
Recent form (all competitions): WWWLLD
There is arguably more pressure on Liverpool's shoulders given that they came from 3-1 down in their quarter-final second leg against Dortmund to win 4-3 at Anfield.
It was one of the most dramatic nights that the Europa League has ever seen, but the Reds need to continue that momentum when they take on Villarreal in the semi-finals.
They are now the favourites to win the tournament, and they have the results to back them up as the Merseyside outfit are the only club to go unbeaten from the start of the group stage to matchday 12 after scooping five wins and seven draws.
For 10 of those matches Klopp has been in charge, but the former Dortmund boss is yet to win a European fixture in Spain having drawn three and lost two.
After their sensational comeback against Dortmund, Liverpool went on a decent run in the Premier League. First up - with a much-changed starting XI - the Reds sealed a 2-1 victory over Bournemouth.
Three days later, Divock Origi, Mamadou Sakho, Daniel Sturridge and Philippe Coutinho scored in a 4-0 rout over Merseyside rivals Everton, which in the end looked more like an exhibition match for the Reds.
Last weekend, though, defensive errors began to show once again when they relinquished a 2-0 lead to draw 2-2 with Rafael Benitez's Newcastle United, who are fighting for their lives in the relegation zone.
The result came after the news that Sakho could be facing a 12-month ban by UEFA after testing positive for a banned substance.
So, while Liverpool will be confident of progressing into the Europa League final as they are unbeaten in seven games in all competitions, there are still defensive concerns, particularly as they have conceded goals in all but one of their last seven fixtures.
Recent form: DWWDDW
Recent form (all competitions): DWWWWD
Christian Benteke has been included in Liverpool's travelling squad to Spain after spending one month on the sidelines with a knee injury, suggesting that he could make an appearance in tomorrow's match.
Sturridge started on the bench for both games against Dortmund in the quarter-finals as Klopp preferred Divock Origi to lead the line.
However, the England international, who has scored in his last three games, is expected to be in the first XI on Thursday due to Origi being absent with an ankle injury.
Sakho will definitely not be in the squad as Liverpool have opted against selecting the defender for upcoming games while UEFA's investigation into an alleged anti-doping violation continues.
As for Villarreal, Marcelino could be missing three players from his squad on Thursday. One definite absentee is Leo Baptistao, who is carrying an injury.
Villarreal possible starting lineup:
Areola; Mariom Bailly, Ruiz, Rukavina; Suarez, Castillejo, Bruno, Trigueros; Soldad, Bakambu
Liverpool possible starting lineup:
Mignolet; Clyne, Lovren, Toure, Moreno; Allen, Milner; Lallana, Coutinho, Firmino; Sturridge
Head To Head
Villarreal and Liverpool have never met before in a European competition, but they faced one another in a club friendly in 2008, which ended in a goalless draw in Spain.
The Yellow Submarine have not had the best results against English opposition in recent years as they have not won any of their last 10 matches against Premier League clubs.
In total, Villarreal have won three, drawn six and lost four of their 12 UEFA games against English teams, while Liverpool's 32 matches against Spanish teams have ended in 13 wins, 10 draws and nine defeats.
We say: Villarreal 1-1 Liverpool
Results at El Madrigal in the Europa League have proven that Villarreal are tough to beat at home and they are capable of extending their unbeaten run, but they face a tougher test against a resilient Liverpool side, whose best chance of playing Champions League football next season is to win the Europa League. The hosts are likely to score on home turf, but Liverpool could nab an away goal, which would set the tie up nicely heading to Anfield next week.