Drenthe was presented as a Real Madrid player on 13 August 2007 along with fellow Dutchman Wesley Sneijder in a double player presentation at the Santiago Bernabeu. Drenthe made his official Real Madrid debut starting as a central midfielder in the second leg of the Supercopa de España against Sevilla. Drenthe scored the equalizer, similar to a Seedorf long range strike, which was struck from 30-40 yards out, hit the crossbar and the ball crossed the line. However, Real Madrid eventually lost the match 5-3 as Sevilla clinched the cup.

Drenthe played fairly regularly for Real Madrid as left-back or left midfielder at the beginning of the season, but due to the sudden development of Brazilian left-back Marcelo, Drenthe's playing time has become limited. In the Dutch media, there were several reports of clashes between Drenthe and Real coach Bernd Schuster, after the German decided to keep Drenthe out of the squad for several matches, meaning that Drenthe had to sit in the stands instead of the bench. After being left out of the game against Valencia, Drenthe stormed angrily out of the training ground of Real. But after making several appearances since, he was ready to serve his best for Real Madrid. During a match against Real Valladolid, he performed really well by providing an assist to Guti's goal and scoring his first league goal. He has been linked with a move to AS Roma, and to Quique Flores' Benfica, on loan.

Despite rumours of Drenthe leaving the club on loan, he has featured in 15 of Real Madrid first 18 games of the 2008/2009 season, starting the last three games and giving creditable performances despite the clubs inconsistent form and major injury problems. Although recently the Dutch ace has been suffering from anxiety since he was booed by his own supporters during Real's 1-0 win at home to Deportivo La Coruna and has not featured since, although former manager Juande Ramos gave Drenthe his support and insisted he would help the young winger