For both teams, this game will be the first of a triple-header during the international break, with a couple of UEFA Nations League matches to follow, after this friendly.
The Netherlands need two wins in their Nations League group to qualify for the next round, with a home game against Bosnia and Herzegovina followed by a trip to Warsaw to face Poland.
Frank de Boer faces a few injury concerns in his squad, which is not ideal for him in terms of the Netherlands's ambitions in this competition.
During the last international break, which saw De Boer take charge of his first three games for Oranje, they didn't win a single game, and scored just one goal.
A 1-0 friendly loss to Mexico was followed by a 0-0 draw away to the Bosnians and a 1-1 draw against Italy in Bergamo.
The Italy game could prove to be a big moment in De Boer's tenure, as the Dutch were much-improved and created quite a few chances to score.
For Spain, their last game was a shock 1-0 loss to Ukraine in Kyiv. They have largely been impressive in the recent games under Luis Enrique, but face a decisive Nations League week ahead of them as well.
They have a trip to Switzerland followed by Germany's visit to Madrid, so this is also ideal preparation for the Spanish.
Netherlands vs Spain Head-to-Head
The Netherlands have won six out of 11 previous clashes against Spain, while losing four times. Only one game has ended in a draw.
The last clash between these two sides was in March 2015 in a friendly in Amsterdam, when the Netherlands won 2-0, thanks to goals from Davy Klaasen and Stefan de Vrij.
Netherlands form guide: D-D-L-L-W
Spain form guide: L-W-D-W-D
Netherlands vs Spain Team News
It was already known before De Boer announced his squad that Virgil van Dijk and Matthijs de Ligt were ruled out with injury. Since the squad was announced, Jasper Cillessen has had to pull out with injury as well. His replacement was Feyenoord's Justin Bijlow, but he has since withdrawn from the squad too. FC Twente's Joel Drommel has been called up to the squad.
Injured: Virgil van Dijk, Jasper Cillessen, Matthijs de Ligt, Mohamed Ihattaren, Justin Bijlow,
For a second successive international break, Spain are without Thiago Alcantara, with the Liverpool man still not fully fit after an ankle injury. Ansu Fati's knee injury means he is ruled out of the squad as well. Rodrgio is ruled out as well, with the Leeds United striker having tested positive for COVID-19.
Injured: Thiago Alcantara, Ansu Fati, Rodrigo Moreno
Netherlands vs Spain Predicted XI
Netherlands Predicted XI (3-5-2): Tim Krul; Joel Veltman, Stefan de Vrij, Nathan Ake; Hans Hateboer, Frenkie de Jong, Gini Wijnaldum, Donny van de Beek, Daley Blind; Memphis Depay, Luuk de Jong
Spain Predicted XI (4-3-3): David de Gea; Jesus Navas, Sergio Ramos, Pau Torres, Sergio Reguilon; Rodri, Dani Ceballos, Sergio Canales; Adama Traore, Ferran Torres, Gerard Moreno
Netherlands vs Spain Prediction
This is likely to be used by both managers as an experimental clash, and is unlikely to be played at a very high intensity. This is the least important fixture of the international break for both sides, and in a period of fixture congestion for most players in the two teams, this game could end in a rather sedate draw.
Prediction: Netherlands 1-1 Spain