The Arsenal centre-back was taken off on a stretcher in the first half of the 2-2 draw.
And the Gunners are set to reveal the 23-year-old has suffered cruciate-ligament damage that could rule him out for several months.
The former England Under-21 star was hurt in a challenge with Marcus Rashford.
And it is understood his boot was unable to grip on the astroturf around the perimeter of the pitch.
Holding has been was in fine form for Arsenal under Unai Emery, sparking talk of a senior call-up for the Three Lions.
But now he faces a long wait before he can try to impress England boss Gareth Southgate again.
Emery had already revealed club doctors feared Holding had sustained a "big injury" – adding to Arsenal's defensive worries.
France centre-back Laurent Koscielny, 33, has only just returned to training in the past fortnight after rupturing his Achilles seven months ago.
And Spanish left-back Nacho Monreal, 32, has niggling hamstring problems.
Those blows have sent speculation soaring that Emery will look for new defenders in the January transfer window.
Meanwhile, the Gunners dropped to fifth after a point and performance at Old Trafford that Emery was "proud" of.
But they are still eight points and three places above a United side whose own gutsy display justified the axing of their two costliest players, Romelu Lukaku and Paul Pogba.
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