Germany, three-time European champions and World Cup runners-up two years ago, have had a poor build-up to the European Championship, losing 5-1 to Romania and 2-0 to Hungary.
The rivalry between the Dutch and the Germans will put Rudi Voeller's men under even more pressure and Van Nistelrooy is the man to exploit any weakness.
Christian Worns and his central-defensive partner Jens Nowotny hold the key to this battle in Porto's Dragao Stadium against the Manchester United star.
"Van Nistelrooy is a world-class striker. He is good in the air, can shoot with both feet and is quick. But I know we can control him," said the Borussia Dortmund player.
"We will simply have to back each other up, and if one player is beaten the next will have to be waiting."
The Dutch start as favourites against a Germany side criticised for their performances in warm-up games.
However, Worns believes the Dutch whose last match was a home defeat to the Republic of Ireland could be there for the taking.
"We know their strengths. If we allow them to take control and push forward all the time, we could pay the price," he said.
"They have weaknesses too. They do not like to defend and we will have to wait and see how they cope with us forcing them to play our game."
Worns, the most capped defender in the German squad, dismissed claims that this is the weakest Germany side for generations.
"I could not care less what anyone says. It has always been a popular sport to knock the German side. But nobody gave us any chance in the last World Cup, but we reached the final.
"We struggled in our group, but lots of teams did. We are a tournament team and we have proved that again and again over the last 30 years."
This has not been the best preparation for a major tournament for Germany, with in-fighting in the squad.
The worst row has been between goalkeeper Oliver Kahn and the unpredictable second choice Jens Lehmann, whose behaviour at Arsenal raised a few eyebrows last term.
The two fell out and it needed coach Rudi Voeller to have a clear-the-air chat with Lehmann.
"They do not have to go on holiday together, they just need to have a good working relationship."
But since Germany set up camp at Almancil on the Algarve, it has all been peace and light.
Dutch coach Dick Advocaat fears his side are likely to be just as vulnerable as the Germans. Apart from the injured Seedorf, Advocaat has 22 fit players. If Seedorf fails to recover in time, Wesley Sneijder will start.
GERMANY (4-5-1) (probable): Kahn; Friedrich, Worns, Nowotny, Lahm; Schneider, Baumann, Hamann, Ballack, Frings; Kuranyi.
HOLLAND (4-3-3) (probable): van der Sar; Reiziger, Bouma, Stam, van Bronckhorst; Davids, Cocu, Sneijder; Van der Meyde; van der Vaart, van Nistelrooy.
Referee: Anders Frisk (Sweden)