Santana first match in the
Primera División de México was with
C.F. Pachuca on 7 May 2000, against
Toluca. He played with
C.F. Pachuca for almost five years, from 2000 to 2005. He was transferred to
Chivas de Guadalajara for the Clausura 2006 Tournament at the end of 2005. Sergio was a versatile player for
Chivas, playing as a
forward, striker, center attacking
midfielder, and even as a defensive midfielder on occasions. Santana stated his desire to leave Chivas following the arrival of
Carlos Ochoa, and several months later, it was announced that he would go to
Deportivo Toluca F.C. In Santana's first match for
Toluca, he scored a goal against
Monarcas Morelia. The match ended in a draw at a goal each. On June 17, 2009, during the Mexican Football draft in Cancun, the Monterrey announced that Santana was to join their squad. With Monterrey, he won a couple of championships and a Concacaf Champions League in 2010. Santana's last Mexican club was
Club Atlas. He had a poor performance, as did the entire squad, in the Clausura 2012. On 24 August 2016, Santana played his last game against
Club América in a group stage match of the
2016 Copa MX Apertura. He was the captain and was replaced at the 44th minute. He finished up his career with a total of 451 matches and having played with nine clubs. ==International career==