Marcus Rashford and Bukayo Saka have both been ruled out of England's World Cup qualifiers against Albania and Poland, the Football Association announced Friday.
England launched their bid to play in the finals of Qatar 2022 with a comprehensive 5-0 thrashing of minnows San Marino at Wembley on Thursday.
Rashford and Saka both missed that match and the FA have now confirmed the pair will miss England's other two qualifying matches this month.
England travel to Tirana on Sunday and face Poland at Wembley on Wednesday - their last fixture before manager Gareth Southgate names his squad for this year's Covid-delayed European Championships.
"Marcus Rashford and Bukayo Saka will play no part in England's forthcoming 2022 FIFA World Cup qualifiers," the FA said in a statement.
"Rashford reported to St. George's Park with an injury that ruled him out of the 5-0 win against San Marino and, following further assessment, it has been decided he will continue his rehabilitation with Manchester United.
"Saka had remained at Arsenal for further assessment on an ongoing issue with the hope of joining up with the Three Lions but will now not be available for the fixtures against Albania and Poland."
Arsenal teenager Saka made his England debut against Wales in October and has since won a further three caps.
Rashford only appeared in two of England's eight fixtures in 2020 and has now been ruled out with a foot injury that made him miss Manchester United's FA Cup quarter-final defeat at Leicester.
"Well, they're both doubtful (for this triple-header)," Southgate said on Wednesday.
"I'd say Marcus is more doubtful than Bukayo at the moment but we're going to assess them.
"Marcus has been very keen to be with us. He obviously wasn't with us so much in the autumn so I think he's been keen to be part of the group and get with us."