The incident occurred after a duel with Wolves defender Hugo Bueno, when Simons fell to the turf, grabbed his knee, and began screaming in pain. Although he returned to the pitch after initial medical treatment, it soon became clear he could not continue the match and was carried off on a stretcher.
An official diagnosis has yet to be confirmed, but initial assessments suggest a possible anterior cruciate ligament injury, which could sideline him for up to a year.
Spurs manager Roberto De Zerbi gave a cautiously optimistic statement after the match.
"I spoke with the doctors, but we still don't have an exact diagnosis. Tests will follow on Monday and Tuesday. He felt pain, but he says he feels better now than at the time of the injury," De Zerbi said, also commenting on Dominic Solanke, who also left the pitch due to injury, but without a stretcher.
A potentially serious injury to Simons is an additional concern for Netherlands national team coach Ronald Koeman, especially with the World Cup approaching.
Koeman is already facing a series of squad issues; Frenkie de Jong, Emmanuel Emegha, Matthijs de Ligt, Mark Flekken, and Jeremie Frimpong already missed the March matches.
An additional blow is the injury to Jerdy Schouten, the captain of PSV Eindhoven, who tore his anterior cruciate ligament in early April and has already been ruled out of the World Cup.
Detailed examinations are expected in the coming days to determine the severity of Simons' injury and whether the Netherlands will lose another key player ahead of the major tournament.