Ronald Koeman's men have fallen behind their rivals after a difficult few years, but arrive in Brussels on a high following an emphatic 3-0 victory over Germany.
Having failed to win any of the previous seven encounters between the sides, they are available at 17/5 (4.40) with William Hill to regain bragging rights by coming out on top for the first time since 1997.
However, Roberto Martinez's men are in equally good spirits after following up their third-place finish at the World Cup with three consecutive victories and are 3/4 (1.75) favourites to make it four in a row here.
Five of the most recent seven meetings between the sides have resulted in draws, and you can get odds of 14/5 (3.80) on them cancelling each other out once again in this one.
Virgil van Dijk has returned to Liverpool as he looks to recover from a rib injury, with Nathan Ake or Stefan de Vrij in line to replace him.
Similarly, Thomas Vermaelen has withdrawn from the squad after suffering a muscle injury in Friday's friendly win over Switzerland, allowing Dedryck Boyata a chance to step in.
While the star-studded Red Devils have just enjoyed an exciting World Cup campaign, their opponents have failed to qualify for the last two major tournaments and find themselves in a transitional phase.
Although this superior quality should see them to victory, recent performances suggest goalmouth action may not be restricted to one end of the pitch.
Considering 10 of Belgium’s last 13 and six of the Netherlands’ last seven competitive matches have produced over 2.5 goals, odds of 29/20 (2.45) offer solid value on the former coming out on top in a match that produces at least three in Brussels.