The 21-year-old, who started in last weekend's league defeat to Brighton, missed Tuesday's 1-0 Champions League group stage victory over Benfica and will not return until after the upcoming international break.
The setback adds to a growing list of absentees for Maresca, who is already without Cole Palmer, Tosin Adarabioyo, Liam Delap and Dario Essugo.
Both Palmer and Adarabioyo are expected to remain sidelined until after the internationals, ruling them out of Saturday's Stamford Bridge clash with Liverpool.
Santos' injury is particularly untimely, as he had been handed increased responsibility in midfield this term. His absence leaves Chelsea light in central options at a crucial point, with the team aiming to build momentum in both domestic and European competitions.
"We lost from Brighton Andrey Santos, who will be out until after the international break. We have seven, eight players out unfortunately for us in this moment," said Maresca, according to Football.London.
The situation underscores concerns raised by Chelsea's directors earlier in the year, when they were warned of possible fitness issues following the club's packed summer calendar.
A gruelling pre-season, which included the Club World Cup, has seemingly begun to take its toll just weeks into the 2025/26 campaign.
Morgan Rogers believes Xabi Alonso has made Chelsea an "exciting" team after the Blues continued their impressive start to the season with a 6-3 victory over Leeds in the League Cup on Wednesday.
Xabi Alonso has moved quickly to dismiss concerns over Levi Colwill's fitness after the Chelsea centre-back was withdrawn during the 6-3 Carabao Cup win over Leeds United.
Andoni Iraola has eased concerns over Bradley Barcola and Milos Kerkez after both players were forced off during Liverpool's 2-1 Champions League victory over Atletico Madrid at Anfield on Wednesday.
Chelsea secured their place in the fourth round of the EFL Cup with a thrilling 6-3 victory over Leeds United at Stamford Bridge on Wednesday night.
