The manager takes the 11-time FA Cup winners to Yeovil in the third round on Sunday barely four months after a humiliating loss to another third-tier team, MK Dons, in the League Cup.
And Yeovil, a south-western town with a population that could fit into United's Old Trafford 76,000-capacity stadium almost twice over, is well known for its football team producing cup giant-killings.
Although some of the biggest scalps happened long ago — memorably in 1949 against then-English power Sunderland — they defined the club as it rose from the non-league to the professional ranks of English football. As a non-league team, Yeovil ousted 20 league sides, according to the FA, though they were routed 8-0 in 1949 by United.
The chance for unlikely revenge has finally come.
"I was over the moon when we were drawn against Manchester United," Yeovil manager Gary Johnson said. "I was in the house watching the draw with my wife and we both jumped up in the air and high-fived each other."
As for beating the Premier League's third-place team?
"We'd need a miracle to pull it off," Johnson said. "But the FA Cup is the FA Cup, that's the beauty of it ... nobody knows what's going to happen."
Indeed, Yeovil's website has documented United's cup shocks in a "Giants Killed" section — highlighting losses to other third-tier sides: from Bournemouth and Leeds in the 1981 and 2010 third rounds respectively.
"I had the same experience against MK Dons, who are also in League One," Van Gaal said. "You never know in a cup match, you have to win because you're out if you lose. We have to beat Yeovil but every team in England wants to beat Manchester United so it will be difficult.
"Everything about playing a lower league team will be different — the pitch, the stadium. For the players, it's more difficult to prepare for a match like this, especially after playing so much over Christmas."
But it's been a grueling period for every team, which is preparing for its fourth game in barely two weeks. Here's a look at some of the other third-round fixtures:
The team standing in the way of holder Arsenal reaching the fourth round is the Hull team it beat in the final in May. Unless Arsenal's defending improves, the trophy could be surrendered on Sunday.
Arsene Wenger is expected to rotate his squad after a 2-0 loss at Southampton on Thursday saw Arsenal drop to sixth in the Premier League.
"We were again haunted by the ghost of what we have seen since the start of the season," Wenger said of Arsenal's defending at Southampton. "This is not the first time it has happened. We did not defend well enough in the final third, and we paid a heavy price. It is a self-inflicted defeat."
THE PREMIER LEAGUE POWERS
In a break from their title tussle, leader Chelsea and second-place Manchester City play second-tier teams on Sunday.
City takes on Sheffield Wednesday, while Chelsea is at home to Watford fresh from a 5-2 loss at Tottenham but key players like striker Diego Costa are likely to be rested with the league the priority,
"Obviously we want to try to beat Watford, but at the same time we have to analyze the players' condition and make the right decision for them," Mourinho said.
Seventh-tier Blyth Spartans, the lowest-ranked team in the draw, is at home to Birmingham of the second-tier on Saturday.
Tony Pulis will take charge of West Bromwich Albion for the first time against Gateshead of the fifth-tier semiprofessional League Conference.
"Obviously West Brom are not having the season they want and there was a bit of unrest there and we were hoping it was going to stay that way for at least another week," Gateshead manager Gary Mills said. "But now they have a new manager in place which will give everyone a massive lift."
Crystal Palace is yet to confirm Alan Pardew as Neil Warnock's successor but he has been heavily involved around the club ahead of Saturday's trip to Dover, another Conference club.
"The lawyers are finalizing the contract," Palace caretaker manager Keith Millen said of Pardew's appointment. "The paperwork is taking longer than expected."