The five-time Ballon d’Or winner is expected to feature against the Magpies at Old Trafford, 12 years after his last appearance for the club.
But Merson believes that the Toon Army will refuse to roll over without a fight, and highlighted Allan Saint-Maximin as one player in particular who could throw a spanner in the works for the hosts.
Speaking on Sky Sports’ Soccer Saturday, the former Arsenal star said: “If he [Ronaldo] wins the Premier League at Manchester United, this will be the biggest thing he’s ever done, in my opinion.
"This is the hardest league in the world. They’re playing Newcastle today, and if Saint-Maximin gets going, it could be a problem. It’s a hard game.
"Newcastle are not turning up here and saying, ‘Let’s write this game off and we’ll go in the next one’. That’s what they do in the other countries.
"That’s why this product, the Premier League, is all around the world. Everybody loves it. Every game is a game.
"I can’t wait to watch it. But he needs to score today. If he doesn’t score today, I would be worried as a Man United fan.
"This is a prime game. If I could pick a game, this is one of them – Newcastle at home. You’re going to have 5,000 Newcastle fans there hoping he gets four!”