Intrusive rocks related to porphyry copper mineralization are part of the wide diversity of subduction-related, mantle-derived, igneous rocks generated in convergent margin settings. What differentiates them from barren igneous rocks results ultimately from the multi-component and multi-stage processes that condition magma composition in these settings. Unfortunately, the petrogenetic history is largely obscured by the pervasive alteration that affects rocks in these deposits. We address this issue through the study of zircon grains from El Teniente, one of the largest known porphyry Cu–Mo deposits in the world. El Teniente belongs to the Miocene–Pliocene Cu–Mo belt of the Central Chilean Andes, which formed in a short timespan during the Cenozoic constructive period of the orogen. Previously U–Pb dated zircon grains were selected for re-examination of their morphological characteristics and in situ analysis of chemical (rare earth element, Hf, Y and Ti contents) and isotopic (Hf, O) composition. They are from six intermediate to felsic syn- to late-mineralization, intrusive units covering a timespan of ∼1·6 Myr. The El Teniente zircons have compositional and morphological characteristics indicating crystallization from a series of cogenetic melts. However, a minor hydrothermal imprint is documented in the presence of crystals with mottled surfaces that correspond to thin high U–Th overgrowth rims (low-luminescent features in cathodoluminescence images). In terms of any other chemical and isotopic characteristic, these are indistinguishable from the main mineral populations. Zircons define morphological and chemical trends reflecting an evolution towards more differentiated magma compositions, lower crystallization temperatures and increased cooling rates with decreasing age of intrusion. Hf and O isotopic compositions are remarkably uniform at grain, sample and deposit scale. This, together with the general absence of older inherited zircon components, the lack of correlations between isotopic signature and whole-rock composition and high initial ε_Hf values (total average 7·4 ± 1·2; 2σ), rules out involvement of any significant crustal contamination in the genesis of the El Teniente magmas. The Hf isotopic composition indicates a relatively juvenile source, but with some crustal residence time. The δ¹⁸O_Zrc weighted mean of 4·76 ± 0·12‰ (2σ; 61 analyses) is at the lower limit of the normal mantle zircon range of 5·3 ± 0·6‰ (2σ), and might reflect crystallization from low-¹⁸O magmas. Hf isotopic compositions have a restricted range in initial ε_Hf values between +6 and +10, identical to preceding Cenozoic barren magmatic activity in Central Chile. These igneous rocks are the product of nearly 25 Myr of subduction-related magmatic activity, developed under contrasting tectonic regimes and margin configurations. This suggests a primary control of the isotopic signature by a stable long-lived MASH-type (melting, assimilation, storage and homogenization) reservoir in the deep lithosphere. In the context of the Cenozoic evolution of Central Chile we argue that dehydration melting in the enriched MASH reservoir occurred as a consequence of increasing crustal thickness, and was prompted by a high-temperature thermal regime resulting from long-lasting preceding magmatism. This process can also fractionate O to generate low-¹⁸O magmas. At the time of El Teniente formation, dehydration melting occurred coevally with arc migration, which probably influenced the fertility of the magmas by increasing the melt component derived from this process relative to the component derived from primary basalt differentiation. At a regional scale, such reactions are expected to occur as a consequence of progressive crustal thickening during the constructive period of the Andes, and can explain the simultaneous generation of porphyry deposits in the Miocene–Pliocene Cu–Mo belt of Central Chile.