The late Miocene to early Pliocene mineralized centers of the Rio Blanco-Los Bronces porphyry copper cluster constitute the largest known copper concentration in the Earth’s crust. Based on new district-scale geological mapping and cross-section interpretation, this study describes the structural evolution of the Main Cordillera of central Chile in the Rio Blanco-Los Bronces district and its relationship with the emplacement of magmatic bodies and mineral deposits. The tectonic evolution of this Andean segment was strongly controlled by regional-scale fault systems, oriented oblique to the north-south axis of the orogen. These NW- and NE-striking faults were active as normal faults during the late Eocene-Oligocene, and controlled the compartmentalization of the Abanico volcanotectonic basin into individual subbasins with characteristic volcanosedimentary facies and thicknesses. The faults were selectively reactivated during Mio-Pliocene east-west contraction, with the NW-striking faults showing a composite reverse-sinistral movement and the NE-striking faults showing mainly dextral strike-slip movements. This reactivation occurred coeval with the deposition of the Farellones Formation and the emplacement of the Rio Blanco-San Francisco batholith, the last pulses of which are genetically related with the formation of the Rio Blanco-Los Bronces cluster. Magmatic and hydrothermal fluid flow was channeled and focused by both sets of preexisting oblique structures and, in turn, fault rupture was driven by high fluid pressures. A proper understanding of similar long-lived, regional-scale arc-oblique fault systems might clarify the structural controls on magmatism and mineralization in the broader Mio-Pliocene metallogenic belt of central Chile and also in other Andean segments.