Pogba's recovery from an ankle injury has been compounded by illness and there is no chance of him featuring against the U's as United look to book their place in the semi-finals of the competition.
Having fuelled speculation about his future during a summer of intense scrutiny, the 26-year-old has not featured since September due to an ankle injury that has restricted him to just six appearances this season.
United manager Solskjaer has spoken confidently about the Real Madrid target returning to action before the end of the year and Pogba had been due to resume first-team training this week, only to succumb to a new problem.
Pogba will again be sidelined as United take to the field on Wednesday, when Diogo Dalot could make his first appearance in 10 weeks.
Marcos Rojo, Timothy Fosu-Mensah and Eric Bailly remain sidelined as United look to progress past the League Two side.
"Any player or any team - and for us now it's a good team that's building - would benefit a lot from winning a trophy or getting to a final, of course winning it is major," Solskjaer said.
"Now we've got a chance of getting into the semis so for us this game is a big one."
Solskjaer plans to make changes and rotate against Colchester, but pledged the side will be strong enough to win the game, "create chances and hopefully score goals".
Mason Greenwood could well playing a starring role again on Wednesday, having followed up a brace and man-of-the-match display in the Europa League against AZ Alkmaar by hitting the leveller against Everton.
Colchester boss John McGreal has no new injury worries ahead of the trip to Old Trafford.
Long-term absentee Paris Cowan-Hall is still out with a Achilles problem although he is back in training.
Colchester have already eliminated Tottenham and Crystal Palace on their way to the last eight and McGreal's men will have their eyes on another major scalp.