US skipper Christian Pulisic has been ruled out of the matches against Canada and Cuba after suffering a hip injury.
The Chelsea winger was replaced on 80 minutes as the Blues led Crystal Palace by two goals, with Callum Hudson-Odoi coming on.
He scored the second in the game, with the result staying 2-0.
But the 21-year-old sustained an injury to his hip, causing doubt with Frank Lampard's side facing Manchester City next.
US head coach Gregg Berhalter confirmed his captain will miss the double Concacaf Nations League matches.
Berhalter said: "Christian is officially at this stage ruled out, we just got that information.
"This was a collaborative decision with the club. looking after the best interest of the player.
"These decisions are always difficult because this group and the coaching staff want nothing more than to have Christian here, but it was a risk we weren't willing to take at this time."
Pulisic is on fine form for Chelsea, netting five goals in his last three league games.
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But he leaves the USA trailing by six points against Group A leaders Canada.
Pulisic's side take on the table toppers on Friday, before playing their game in hand against Cuba four days later.
Berhalter's men must win both of their games, and make up a three-goal differential on Canada, in order to qualify for the knockout round.
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