The Uruguay striker is also set to miss the trip to Everton next Wednesday after returning to his homeland as his partner is due to give birth.
Hernandez was an unused substitute in last Sunday's 2-1 home defeat to Tottenham and he will play no part at Old Trafford as Hull strive to deny United a 10th consecutive victory over them this weekend.
"There's one absentee and that's Hernandez," said Hull boss Steve Bruce. "He's gone to Uruguay to go and bring his baby home, who will be delivered today [Friday].
"Then he's got to go and register and bring the baby back to England. He'll be missing Saturday and probably Wednesday."
Mohamed Diame is available to return after the midfielder recovered from a knee injury.
Bruce has never secured all three points against United during his managerial career and hopes his luck will change at Old Trafford.
"I think I'm due a result and maybe without Sir Alex [Ferguson] being there, I might have a chance," said the former United captain.
"I've been going a long time and I've never been able to beat them. I've had a couple of draws but that's about it.
"I need everyone to play to a level that will cause Manchester United problems and hopefully we can catch them on a bit of an off-day."
Bruce's side are just a point above the relegation zone after losing their last three matches.
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