Nigel Adkins Blades sit just outside the third tier play-offs with a 47-place gap between the two sides, but they will be highly motivated to cause a major upset on their first visit to Old Trafford in 12 years.
Phil Jones is injured and will miss out but Jesse Lingard is fit again and available for selection after a hamstring injury.
Adnan Januzaj has returned from a disappointing loan spell at Dortmund but seems unlikely to feature in this match after LVG confirmed the Belgian will start for the Under 21s against Reading on Monday.
Long term trio Antonio Valencia, Marcos Rojo and Luke Shaw remain sidelined but are progressing well.
Having ended an eight-game winless run last weekend, Van Gaal called for his side to build on that victory over Swansea, and said:
"We have always played attacking football but now we have scored and that is the difference.
"The victory against Swansea gave us confidence but we have to see that again and one swallow does not make a summer.
"The FA Cup is very difficult to win as we saw last season against Yeovil and Cambridge United also, every match in it is difficult to win no matter what the level and you always have to compete so that is what we shall do
"Januzaj shall play with the Under 21s on Monday as he needs match rhythm but I believe in his talent so we have to wait and see."
The 'other United' from across the Pennines have forged something of a reputation as giant-killing cup specialists in recent years having knocked out Premier League duo West Ham and Southampton en route to the last four of the League Cup last term where they were narrowly edged out by Tottenham.
In 2013/14, The Blades enjoyed a lengthy run in this competition, putting out higher division trio Aston Villa, Fulham and Nottingham Forest only to fall at the semi-final hurdle in an eight goal thriller with Hull.
It's hard to see Adkins outfit repeating these heroics at Old Trafford but their giant-killing exploits should serve as a reminder that this is the FA Cup and anything can happen.
Form guide: United L L L L D W Sheff Utd D W W W W L
Match odds: United 9/4 Draw 4/1 Sheff Utd 13/5
Referee: Jonathan Moss
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