Simons, 23, went down after a challenge with Hugo Bueno in the 63rd minute. He attempted to run off the injury but collapsed again and was taken from the field on a stretcher, unable to finish the match. Lucas Bergvall came on as his replacement.
Head coach Roberto De Zerbi said after the game: "I hope both are not too important problems, especially for Xavi, because Solanke is a muscular injury. I hope Xavi's injury is not too serious. We have to wait."
Dominic Solanke had already been forced off before half-time with a muscular problem. His absence also carries England World Cup implications with the tournament just seven weeks away.
João Palhinha settled the match with an 82nd-minute header as Tottenham registered their first league win of 2026. The result kept them inside the relegation zone on 34 points but reduced the gap to West Ham United in 17th to two points with four games remaining.
Simons has been one of Tottenham's standout performers in a difficult season, contributing two goals and five assists across 28 Premier League appearances. The Netherlands international was expected to be a key figure under Ronald Koeman at the World Cup and his potential absence would represent a major blow to both club and country.