Noni Madueke was spotted leaving Wembley Stadium with a brace fitted around his left knee following England's Friday night fixture against Uruguay.
The Arsenal attacker, who sustained the problem during the first half of the 1-1 draw, hobbled through the mixed zone after the match with the protective support clearly visible.
The 24-year-old is anticipated to withdraw from Thomas Tuchel's squad ahead of Tuesday's friendly against Japan and return to Arsenal's London Colney training base instead.
His early departure from the international camp represents a significant setback as the former Chelsea player had been hoping to strengthen his case for World Cup selection.
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The injury occurred during the 33rd minute when Madueke attempted to drive into the Uruguayan penalty area from his position on the right flank.
As the winger cut inside and prepared to shoot, defender Rodrigo Aguirre tracked back to make a challenge, winning the ball but following through heavily into the Arsenal player.
Madueke collapsed to the turf following the impact and required extensive attention from England's medical staff before eventually rising to his feet.
There were muted appeals for a foul from the home side, but the match official allowed play to continue without awarding a free kick.
Noni Madueke was spotted leaving Wembley Stadium with a brace fitted around his left knee following England's Friday night fixture against Uruguay
|GETTY
Despite his determination to carry on, Madueke's efforts proved futile as he went down again just minutes later without any contact from an opponent.
The winger signalled to the physios that he could not continue and requested a substitution.
West Ham's Jarrod Bowen came on in the 38th minute.
Madueke was assisted from the pitch and proceeded directly down the tunnel towards the dressing room, at one point holding his jaw as he departed.
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Noni Madueke sustained the problem during the first half of the 1-1 draw
|GETTY
The sight of the attacker bypassing the substitutes' bench entirely will have caused concern for both Tuchel and Arsenal manager Mikel Arteta.
The setback compounds an already difficult situation for his club manager.
He had six players unavailable for international duty during the current break.
Eberechi Eze, Leandro Trossard, Gabriel, William Saliba, Jurrien Timber and Martin Odegaard were all absent from their respective national squads through injury.
The injury occurred during the 33rd minute when Madueke attempted to drive into the Uruguayan penalty area from his position on the right flank
|GETTY
Madueke's fitness concern now raises doubts over his availability for Arsenal's FA Cup quarter-final clash with Southampton on April 4.
The timing is particularly unfortunate for the Spanish manager.
The north London side are currently pursuing a potential trophy treble.
They lead the Premier League and maintain strong positions in both the FA Cup and the Champions League.
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