The Sanandaj-Sirjan zone (SSZ) of Iran comprises sedimentary and metamorphic basement rocks, which are generally regarded as having been derived from the southern active margin of the Eurasian plate. Within the SSZ, a number of Mesozoic to Cenozoic granitoid intrusions of various size, elongated in a NW-SE direction are exposed. With the benefit of precise age dating, geochemical and isotopic data over the past decade, the magmatic history of these intrusions has become clearer. This study presents further geochronological and geochemical data for previously dated and undated granitoids together with considerable zircon Lu-Hf isotopic data, which were limited in the past. Combined with previous work, these new data, including the finding of ca. 170 Ma adakite, lead to improved constraints on the Meso-Cenozoic tectonic evolution of Neo-Tethyan lithospheric subduction. The dominant early-middle Jurassic magmatism is proposed to have occurred with a major contribution of crustal components during the initiation of Neo-Tethyan subduction. Subsequent, late Jurassic magmatism suggests the involvement of lower crust partial melting in an extensional tectonic setting. Cretaceous magmatism almost ceased after formation of a flat slab, caused by a trench retreat rate exceeding that of slab roll-back. Late Paleocene-Eocene magma sources in the SSZ are dominated by mantle-derived input through an asthenospheric window with subordinate crustal contamination during the subduction of the Neo-Tethyan ridge-spreading center. This interpretation differs from Paleocene-Eocene magmatic flare-up proposed for the northern Iranian interior, which may have been driven by an episode of slab retreat or slab roll-back following Cretaceous flat slab subduction.