Diego Costa and Joao Felix were given the chance to build upon their burgeoning attacking partnership as Diego Simeone selected a strong starting XI.
Atleti fell behind in the 11th minute as Nicolas Ibanez converted a rebound when Luis Reyes' shot came back off the post, Jan Oblak having initially failed to deal with an over-hit backpass from Felipe.
Costa controlled Joao Felix's sumptuous lofted pass to crash a volley against the crossbar but the hosts remained ahead until Simeone sent on a number of his youngsters.
Two of them combined to equalise in the 72nd minute, 18-year-old forward Sergio Camello powering home Carlos Isaac's cross.
The winner arrived six minutes from time, with Juan Portales putting through his own goal after Manu Sanchez and Rodrigo Riquelme unpicked San Luis.
Simeone's men face Juventus next Sunday (AEST) in the International Champions Cup before hosting Getafe the next weekend in their LaLiga opener.