After just 70 seconds, the Barcelona player scored the opening goal when Croatia visited Seville.
Dion Beljo did equalise with a header in the 28th minute, but three minutes later Yamal stepped forward again.
The teenager delivered a perfect cross and teammate Marc Pubill headed in the 2-1 goal.
After 65 minutes, Yamal scored his 10th international goal in 35 appearances. He fired home from a tight angle to make it 3-1 before Nico Williams sealed the victory at 4-1 in the closing stages.
Spain top Group 3 in Division A with a maximum six points. England bounced back from a 3-2 loss to the Spaniards in their Nations League opener last time out, with goals from Anthony Gordon and Harry Kane in a 2-0 win away to the Czech Republic.
