A massive test for the Mancs, which can only help Newcastle's cause on Saturday.
The Magpies play at Old Trafford in the early kick-off.
Man Utd have picked up maximum points from two games, but have hardly impressed, having only recorded three shots on target in two games.
If they struggle tonight I'm sure Newcastle will benefit, but if they find their shooting boots and chalk up a big score, their confidence will come on in leaps and bounds.
So it's a double-edged sword.
Ordinarily the visit of the runners-up in the Belgian league would not cause much of a stir, but Van Gaal is under no illusions about the price of failure in the two-legged fixture, which concludes next Wednesday in Bruges.
Van Gaal worked tirelessly to turn United into a top-four team following their seventh-placed finish under David Moyes, but defeat would send the three-time European champions into the Europa League - and that is something neither the manager nor the board wants.
"Of course," Van Gaal said when asked if this was his most significant fixture as United boss.
"I have already explained, the players want to participate (in the Champions League) and the board wants to participate, but especially the fans want to participate so the pressure is high."
History suggests United should have an easy ride. The aggregate score of their last three home games against Belgian opponents is 18-1.
Brugge's squad has been decimated by injury in the build-up to the match, and they needed a stoppage-time winner to beat KV Kortrijk on Friday.