With six games remaining, Valencia find themselves just two points clear of the drop zone, while Villarreal sit five points shy of the top four.
Match preview
When Valencia secured back-to-back wins over Elche and Real Valladolid at the end of last month, it looked as though Ruben Baraja's side would steer clear of relegation trouble, but Sunday's defeat at Cadiz has halted their momentum.
Despite racking up 16 shots while enjoying the lion's share of possession, Valencia suffered a 2-1 loss at Estadio Nuevo Mirandilla last time out, as Samuel Lino's second-half strike failed to spark a comeback for the visitors.
Not only have Los Che lost four of their last seven La Liga matches, but they have also lost 12 of their previous 18, collecting just four wins along the way, although they have continued to pick up positive results on home soil.
Indeed, Valencia have suffered a solitary defeat in their last five games at the Mestalla, securing 1-0 victories over Real Sociedad and Osasuna before coming from behind to defeat Valladolid 2-1 last week.
Valencia last suffered relegation back in 1985-86 and have won two La Liga titles since then, but they are now in real danger of dropping into the second tier for the first time in almost four decades.
At the opposite end of the table, Villarreal are chasing a top-four finish for the first time since 2015-16, having finished fifth on three occasions in the past six seasons to establish themselves as a genuine force in Spanish football.
After thrashing Espanyol 4-2 on Thursday, Quique Setien's side claimed a 3-1 victory over Celta Vigo on Sunday, with Nicolas Jackson bagging a brace in the opening 12 minutes to set up the win for his side.
In addition to winning each of their last two La Liga matches, Villarreal have won five of their previous seven, with victories over Osasuna, Real Sociedad and Real Madrid preceding last week's wins.
Better still, the Yellow Submarine have lost just two of their last 10 league outings, notching seven victories in the process, and they are now the fourth-highest scorers in the division thanks to a series of dominant displays.
Having won three of their past four away games - including a famous 3-2 victory at the Bernabeu last month - Villarreal will be confident of adding more points to their growing tally at the Mestalla.
Valencia La Liga form:
D
L
L
W
W
L
Villarreal La Liga form:
W
W
L
L
W
W
Team News
Valencia look set to be without the injured duo of Justin Kluivert (leg) and Marcos Andre (knee) for the foreseeable future, while Francisco Perez (back) is a doubt for Wednesday's clash.
With two forwards sidelined and another unlikely to feature in midweek, Hugo Duro is expected to lead the line for the hosts, although veteran striker Edinson Cavani could get the nod in attack.
American youngster Yunus Musah will continue in midfield, having featured in all but three of Valencia's La Liga clashes this season while enhancing his reputation.
As for Villarreal, Francis Coquelin (knee) has been ruled out for the season, with Jose Luis Morales (knee) joining the former Arsenal midfielder on the club's injury list.
There are also question marks over the availability of Kiko (muscle) and Gerard Moreno (forward), so Nicolas Jackson is expected to continue in attack, with Samuel Chukwueze, Giovani Lo Celso and Yeremy Pino supporting the lone striker.
Juan Foyth and Alberto Moreno will occupy the full-back roles, while experienced goalkeeper Pepe Reina will continue between the sticks.
Valencia possible starting lineup:
Mamardashvili; Foulquier, Cumart, Diakhaby, Ozkacar, Lato; Musah, Moriba, Gonzalez, Lino; Duro
Villarreal possible starting lineup:
Reina; Foyth, Mandi, Torres, Moreno; Parejo, Capoue; Chukwueze, Lo Celso, Pino; Jackson
We say: Valencia 1-2 Villarreal
Fighting for their lives at the bottom end of the table, Valencia will be desperate to pick up a positive result on Wednesday, but in-form Villarreal will not make life easy for the hosts.