The composite Meghri-Ordubad and Bargushat plutons of the Zangezur-Ordubad region in the southernmost Lesser Caucasus consist of successive Eocene to Pliocene magmatic pulses, and host two stages of porphyry Cu-Mo deposits. New high-precision TIMS U-Pb zircon ages confirm the magmatic sequence recognized by previous Rb-Sr isochron and whole-rock K-Ar dating. A 44.03 ± 0.02 Ma-old granite and a 48.99 ± 0.07 Ma-old granodiorite belong to an initial Eocene magmatic pulse, which is coeval with the first stage of porphyry Cu-Mo formation at Agarak, Hanqasar, Aygedzor and Dastakert. A subsequent Oligocene magmatic pulse was constrained by U-Pb zircon ages at 31.82 ± 0.02 Ma and 33.49 ± 0.02 Ma for a monzonite and a gabbro, and a late Miocene porphyritic granodioritic and granitic pulse yielded ages between 22.46 ± 0.02 Ma and 22.22 ± 0.01 Ma, respectively. The Oligo-Miocene magmatic evolution broadly coincides with the second porphyry-Cu-Mo ore deposit stage, including the major Kadjaran deposit at 26-27 Ma. Primitive mantle-normalized spider diagrams with negative Nb, Ta and Ti anomalies support a subduction-like nature for all Cenozoic magmatic rocks. Eocene magmatic rocks have a normal arc, calc-alkaline to high-K calc-alkaline composition, early Oligocene magmatic rocks a high-K calc-alkaline to shoshonitic composition, and late Oligocene to Mio-Pliocene rocks are adakitic and have a calc-alkaline to high-K calc-alkaline composition. Ragiogenic isotopes reveal a mantle-dominated magmatic source, with the mantle component becoming more predominant during the Neogene. Trace element ratio and concentration patterns (Dy/Yb, Sr/Y, La/Yb, Eu/Eu*, Y contents) correlate with the age of the magmatic rocks. They reveal combined amphibole and plagioclase fractionation during the Eocene and the early Oligocene, and amphibole fractionation in the absence of plagioclase during the late Oligocene and the Mio-Pliocene, consistent with Eocene to Pliocene progressive thickening of the crust or increasing pressure of magma differentiation. Characteristic trace element and isotope systematics (Ba vs. Nb/Y, Th/Yb vs. Ba/La, 206Pb/204Pb vs. Th/Nb, Th/Nb vs. δ18O, REE) indicate that Eocene magmatism was dominated by fluid-mobile components, whereas Oligocene and Mio-Pliocene magmatism was dominated by a depleted mantle, compositionally modified by subducted sediments. A two-stage magmatic and metallogenic evolution is proposed for the Zangezur-Ordubad region. Eocene normal arc, calc-alkaline to high-K calc-alkaline magmatism was coeval with extensive Eocene magmatism in Iran attributed to Neotethys subduction. Eocene subduction resulted in the emplacement of small tonnage porphyry Cu-Mo deposits. Subsequent Oligocene and Miocene high-K calc-alkaline and shoshonitic to adakitic magmatism, and the second porphyry Cu-Mo deposit stage coincided with Arabia-Eurasia collision to post-collision tectonics. Magmatism and ore formation are linked to asthenospheric upwelling along translithospheric, transpressional regional faults between the Gondwana-derived South Armenian block and the Eurasian margin, resulting in decompression melting of lithospheric mantle, metasomatised by sediment components during the previous Eocene subduction event.