As 11-time winners of the competition and with 75 places between the two sides in the Football League, Van Gaal's men will start the match as strong favourites to progress.
But the Dutchman, who avoided an upset in the previous round with a 2-0 victory at League One Yeovil Town, knows not to expect an easy ride at Cambridge, who are currently mid-table in League Two.
"It's always tough to play, in the mind at least, a weaker team, because in the players' minds it's a weaker team," he said.
"For example, PSV Eindhoven, the number one team in the league in the Netherlands, lost to the number three side in the second division.
"That shall always happen in the FA Cup. There are always surprises, and I hope we are not the surprise.
"When you see Cambridge and analyse them, they play very direct, with long balls, and have five or six players who are over 1.9 metres in height. So for us it will be difficult to defend.
"That is why we have to prepare very well. It's not so easy to play and beat Cambridge United.
"It is another opponent, with another playing style, with other players, and we have to beat them, otherwise we are out.
"It's different more in the atmosphere. The FA Cup is very important to the fans, to the people and to the players also. That is the difference.
"Okay, in Germany it's fantastic that you win the cup, but no so like it is here. Also, the attendances of the fans is much higher than in Germany or Spain."
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