Cristiano Ronaldo struck a brace as Madrid guaranteed themselves a first-place finish in the group after convincingly seeing off the hosts at the Amsterdam ArenA.
Goals from Karim Benzema and Alvaro Arbeloa put Madrid in control and Ronaldo struck twice after the break, the second from the penalty spot.
Madrid finished the match with only nine men after Xabi Alonso and Sergio Ramos were sent off in the closing stages after picking second yellow cards for time-wasting.
Real coach Jose Mourinho said: "It has made me very happy the response of players like Arbeloa, Lass, Albiol and Benzema, who are not regulars. I am very happy to make these changes and their performances were very good.
"I can do it more times this season. But on Monday (against Barcelona) it will different, we do not need motivation, you'll have to wait and see what happens."