The Mesozoic tectono-thermal evolution of eastern South China plays an important role in forming the abundant magmatic rocks and associated giant polymetallic deposits. The middle-late Mesozoic granitoids in Mufushan and adjacent regions (e.g., Lianyunshan, Wangxiang, Taohuahsan, etc.) represent the western front of the southeast China magmatic province. However, the tectonic regimes and petrogenesis of the magmatic rocks are still elusive. Here, we report zircon UPb ages, geochemistry, and Sr-Nd-Hf-Pb isotopic data for the granitic rocks in the Mufushan region, in combination with data available from the literatures, to discriminate the middle-late Mesozoic tectono–magmatic history of the Mufushan complex in north-central South China Block. New zircon UPb dating suggests that the Mufushan two-mica monzogranites were emplaced at 149–144 Ma, a short time after the 153–151 Ma granodiorites. These late Jurassic felsic magmas share broad similarities in geochemical-isotopic characteristics, with significant enrichment in LREEs and LILEs (e.g., Ba, Rb, Th, and K), depletion in some HFSEs (e.g., Nb, Ta, Ti, and P) and positive Pb anomalies, similar to those of arc-type rocks. The common existence of Neoproterozoic zircons within the magmatic rocks indicates a certain amount of ancient material involved in the genesis of the magma. The two-mica monzogranites have εHf(t) values ranging from −13.4 to +3.5, overlapping with those of the granodiorites (−11.3 to +6.6), but both are lower than contemporaneous diorites (−2.4 to +0.59), suggesting a greater incorporation of enriched materials into the source for the granitoids. The two-mica monzogranites and granodiorites have εNd(t) values ranging from −7.9 to −8.8 and − 10 to −7.9, with corresponding two-stage Nd model ages of 1.7–1.6 Ga and 1.6 Ga, respectively, falling within their two-stage Hf model ages of 2.0–1.4 Ga and 1.8–1.4 Ga, respectively. Compared with the geochemical and isotopic compositions of the coeval magmatic rocks in eastern South China, we favor that the late Jurassic Mufushan granodiorites evolved from variable mixing and differentiation of the diorites and granitoids, accompanied by a continuous magma assimilation. The presence of late Jurassic highly fractionated granites suggests an extensive magma differentiation in eastern South China and the well-developed early Cretaceous A-type granites in eastern South China reflect a dominant extensional tectonic regime induced by slab roll-back of the Izanagi plate. The involvement of subduction-related melts facilitated the underplating of mantle-derived magma and crustal heating, triggering intensive partial melting of the lithosphere and magma enrichment, as well as the polymetallic deposits in eastern South China.