The key factor that controls the genesis of porphyry Cu deposits (PCDs) in collisional orogens remains a debated topic. This study employs whole-rock La/Yb proxies to quantitatively constrain the spatial and temporal variations in crustal thickness of the South Armenian–Iranian magmatic belt (SAIMB) within the Zagros orogen (central Tethys region) since the Eocene. Our results show that rapid crustal thickening occurred first in the NW section of the SAIMB at ~35 Ma, then propagated southeastward into the central and SE sections at ~25 Ma and 20 Ma, respectively, indicating that the Arabia–Eurasia collision was diachronous. The formation of the large and giant collision-related PCDs in the SAIMB might have been controlled by the collision process because they developed first in the NW section of the SAIMB and subsequently propagated southeastward into the central and SE sections. More importantly, crustal thickness mapping shows that the PCDs are preferentially developed in the thickened crust areas (>50 km). Our findings propose that thickened crust is critical for the formation of the PCDs in collisional orogens by promoting Fe2+-rich minerals as a fractionating phase, driving magmatic auto-oxidation and releasing Cu into the magmas. The Cu is then partitioned into magmatic fluids, sustaining the porphyry systems. Furthermore, our research highlights that the thickened crust hosting PCDs was characterized by a previously thinner crust (<40 km), where magmas had low oxygen fugacity due to the absence of the auto-oxidation process. Consequently, chalcophile elements (e.g., Cu) efficiently separated from the melt through sulfide segregation, forming large Cu-bearing lower-crustal cumulates. These cumulates can be mobilized with an increase in oxygen fugacity, incorporating into subsequent porphyry mineralization. We thus propose that the crustal thickness evolution over time controls the formation of the PCDs in collisional orogens. There are two essential stages in the collision-related PCDs formation: the first is high-flux magmatism in the thin crustal setting (<40 km), leading to metal-fertilized lower crust through sulfide segregation, and the second is the intracrustal auto-oxidation during crustal thickening (>50 km) which facilitates pre-enriched sulfides in the lower crust to re-dissolve, releasing Cu into the magmas.