The Beiya porphyry-skarn Au deposit is one of the largest gold deposits in China, temporally and spatially associated with Eocene intrusions in a post-collisional setting in western Yunnan, China. In this study, we report new whole-rock geochemistry, Sr-Nd isotope, zircon U-Pb geochronology and in situ zircon Hf-O isotopes of quartz-monzonite and biotite-monzonite porphyries from the Beiya deposit. The porphyry-skarn mineralization at the Beiya deposit is mainly associated with the quartz monzonite porphyry (35.8 ± 0.6 Ma), while the biotite-monzonite porphyry (34.3 ± 0.5 Ma) represents a post-mineralization intrusion crosscutting the main orebodies and the quartz-monzonite porphyry. Both intrusions have high-K and adakitic composition and are characterized by high Sr/Y ratios, high SiO2 and Al2O3 concentrations (SiO2 = 69.80–73.86 wt%; Al2O3 = 14.11–15.19 wt%), and low MgO, Cr, and Ni concentrations (MgO = 0.2–1.0 wt%; Cr = 1.76–11.13 ppm; Ni = 2.52–11.72 ppm). Their Sr-Nd isotope compositions (87Sr/86Sr = 0.7066–0.7077; εNd(t) = ?5.3 to ?1.5) are consistent with the lower crustal-derived amphibolite xenoliths (87Sr/86Sr = 0.7060–0.7100; εNd(t) = ?10.0 to 0.0), indicating that they might be derived from a thickened juvenile lower crust beneath the Yangtze Craton. The biotite-monzonite porphyry has lower zircon δ18O values of +5.3‰ to +6.8‰ and higher εHf(t) values of ?2.3 to +5.5 than those of the quartz-monzonite porphyry with δ18O values of +7.1‰ to +8.2‰ and εHf(t) values of ?3.8 to +1.5, implying that they were derived from different parts of the lower crust. High Ba/La and Pb/Ce ratios suggest that the quartz-monzonite porphyry is derived from a volatiles-rich reservoir. Relatively higher La/Yb, Sm/Yb and Dy/Yb ratios of the biotite-monzonite porphyry indicate residual garnet in the source, indicating a deeper source than that of the quartz-monzonite porphyry. The hydrous components should be represented by the amphibole-rich lithologies, which has relatively shallower depth than that of the garnet-bearing mafic thickened lower crust. Our data suggest that the mineralized quartz-monzonite porphyry at the Beiya deposit is derived from partial melting of amphibole-rich lithologies in the upper part of the thickened juvenile lower crust beneath the Yangtze Craton, while the post-mineralization biotite-monzonite porphyry is derived from the basal, and volatiles-poor, part of the juvenile lower crust.