He started playing for Satelite. After a brief stay at Racing Santander he moved to Real Madrid in 1971 when he was just 19 years old. He remained at the club until his retirement in 1988.
At Madrid, he won 9 La Liga titles, 4 Copa del Rey and 2 UEFA Cups. He played 778 first team matches (a record until Manuel Sanchís surpassed him during the 1997-1998 season) in which he scored 352 goals. He is the 8th highest topscorer of all-time in the Spanish first division (187 goals in 461 matches played with Real), but never won the Pichichi award.
On December 21, 1983, during a European Championship qualifying match against Malta that Spain had to win by 11 goals in order to qualify, Santillana scored a hat trick in the first half and added a fourth in the now historic 12-1 win that saw the Spaniards through at the expense of the Netherlands.