Striker Luis Suarez is suspended and captain Diego Lugano, the mainstay of one of the tournament's toughest defenses, is almost certain to miss the game through injury.
The Uruguayans must find a way to cope with the attacking midfield trio of Arjen Robben, Wesley Sneijder and Dirk Kuyt if they are to record their first World Cup win over European opposition since 1970, when they beat the Soviet Union.
The Dutch will have to put the shackles on striker Diego Forlan, who has looked unstoppable in South Africa.
Netherlands central defender John Heitinga knows Forlan well as the pair played together for a year at Atletico Madrid.
Heitinga's partnership with Joris Mathijsen was a concern before the tournament started but has turned out to be one of the Dutch team's strong points. They have conceded only one goal from open play and two penalties so far.
Right back Gregory van der Wiel is suspended but Khalid Boulahrouz, his likely replacement, is also strong both going forward and defensively. Giovanni van Bronckhorst at left back is naturally a midfielder.
Uruguay's defense has given away only two goals in four games. But, already likely to be short of Lugano, the suspension of Jorge Fucile, excellent at left back, is another blow.
Mauricio Victorino should keep his place and partner Diego Godin, who returns from injury, in central defense. However, based in Chile and with only eight caps, he lacks experience at this level and could find Robin van Persie a handful.
Right back Maximiliano Pereira is solid defensively but does not add much to the attack. Martin Caceres should get his first start at left back but is an unknown quantity. He was a regular in the qualifiers but an injury last year set his career back.
The game is likely to turn on how well Uruguay's midfield handle the Dutch attacking midfield trio of Robben, Kuyt and Sneijder, who undid Brazil in the second half of their 2-1 quarter-final win.
Robben is only a threat if he can get onto his left foot and the Uruguayans are experienced and wily enough to keep him on his right.
With Nigel de Jong suspended, Demy de Zeeuw will partner Mark van Bommel in front of the Netherlands defense, an important role given the way the fullbacks, especially Van Bronckhorst, push forward.
Uruguay's midfield is not the team's strongest point. Their most inspirational player, youngster Nicolas Lodeiro, has not had a happy tournament, having been sent off against France in their opening match and now suffering an injury.
Diego Perez is the midfield strongman and does most of the dirty work while Walter Gargano is also a holding midfielder with stronger technique and distribution. Egidio Arevalo should be the playmaker while Alvaro Pereira adds width on the left.
Van Persie is the lone Dutch striker. He has not had a great World Cup although even when he does not play well he has an important role as a distraction to defenders who also have to deal with the Kuyt-Sneijder-Robben trio just behind him.
Forlan poses the biggest threat to the Netherlands defense. His pace, work rate and skill, not to mention deadly long-range shooting, have made him one of the top players at the World Cup and he already has three goals at this tournament.
Striker Edinson Cavani, who has previously played just behind the front two, is likely to partner Forlan in attack, replacing the suspended Luis Suarez.
