The Manchester United pair, which had been a regular feature under Ronald Koeman, misses out after enduring difficult individual campaigns at Old Trafford.

Koeman's side welcomes Spain to Rotterdam for the first leg of a quarter-final tie on 21 March (AEDT), with the return fixture taking place in Valencia three days later.

When fit, former captain De Ligt had been part of every Dutch squad since making his debut in 2017, while Zirkzee had been involved each time since his senior international bow at UEFA Euro 2024.

Despite the duo's absence, Koeman has still named 10 Premier League players in his provisional 25-man party, including Virgil van Dijk, Cody Gakpo and Justin Kluivert.

Meanwhile, former Manchester United forward Memphis Depay, who is now playing for Brazilian giant Corinthians, could make his first Oranje appearance since the UEFA Euro 2024 semi-final defeat by England.