DeAndre Yedlin has missed the club's last two games after suffering a thigh injury in last month's Championship win over Brighton and Hove Albion.
United manager Rafa Benitez said at the time that the injury was thought to be a small tear.
And the right-back – who has been examined by USA team doctors in Los Angeles – is facing up to five weeks on the sidelines.
Yedlin, signed from Tottenham Hotspur last summer, is pencilled in for a return in late April, when the league leaders could have just two games left to play.
USA head coach Bruce Arena said: “DeAndre has been in LA this past week and examined by our team doctors.
“We realise he is not going to be able to go to these next two matches against Honduras and Panama.
“It is likely he will be out for about five weeks. I would expect he will be back on the field for Newcastle right at the end of this season in April.”
In Yedlin's absence, Vurnon Anita, back from ankle injury, will have an extended run in Benitez's starting XI.
Meanwhile, Benitez – whose side take on Birmingham City at St Andrew's on Saturday – also has a concern over centre-half Ciaran Clark, who limped out of last weekend's home defeat to Fulham with a knee problem.
And right-back Jamie Sterry recently underwent surgery on a groin injury.
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