The 31-year-old was forced off just 13 minutes after being substituted on and faces months on the sidelines and will have to undergo an operation on the injury.
Villarreal has confirmed that Roberto Soldado will require surgery on a serious knee injury sustained in Tuesday's friendly defeat to Deportivo La Coruna.
The 31-year-old was a halftime substitute in the 2-0 loss at the Riazor, but was forced off just 13 minutes later after falling awkwardly and left the stadium on crutches.
The club has since announced that an operation will be required to fix a torn cruciate ligament and meniscus, meaning the striker will likely be sidelined for several months.