Although continental crust is characterized by the widespread occurrence of granitoids, the causal relationship between continental crust growth and granitic magmatism still remains enigmatic. While fractional crystallization of basaltic magmas (with or without crustal contamination) and partial melting of mafic lower crust are two feasible mechanisms for the production of granitoids in continental arc regions, the problem has been encountered in discriminating between the two mechanisms by whole-rock geochemistry. This can be resolved by an integrated study of zircon U-Pb ages and Hf-O isotopes together with whole-rock major-trace elements and Sr-Nd-Pb isotopes, which is illustrated for Mesozoic granitoids from the Gangdese orogen in southern Tibet. The results provide geochemical evidence for prompt reworking of the juvenile mafic arc crust in the newly accreted continental margin. The target granitoids exhibit high contents of SiO2 (65.76–70.75 wt%) and Na2O + K2O (6.38–8.15 wt%) but low contents of MgO (0.19–0.98 wt%), Fe2O3 (0.88–3.13 wt%), CaO (2.00–3.82 wt%), Ni (<5.8 ppm), and Cr (≤10 ppm). They are enriched in large ion lithophile elements, Pb, and light rare earth elements but depleted in high field strength elements. The granitoids are relatively depleted in whole-rock Sr-Nd isotope compositions with low (87Sr/86Sr)i ratios of 0.7043–0.7048 and positive εNd(t) values of 0.5–2.6, and have relatively low 207Pb/204Pb and 208Pb/204Pb ratios at given 206Pb/204Pb ratios. Laser ablation–inductively coupled plasma–mass spectrometry and secondary ion mass spectrometry U-Pb dating on synmagmatic zircons yield ages of 77 ± 2–81 ± 1 Ma in the Late Cretaceous for their emplacement. Relict zircons have two groups of U-Pb ages in the late Mesozoic and the late Paleozoic, respectively. The whole-rock Sr-Nd isotopes in the granitoids are quite similar to those of Late Cretaceous mafic rocks in the Gangdese batholith. In addition, both synmagmatic zircons and relict zircons with Late Cretaceous U-Pb ages exhibit almost the same Hf-O isotope compositions to those of the slightly earlier mafic rocks. All these observations indicate that the granitoids were mainly derived from partial melting of the juvenile mafic arc crust. Therefore, reworking of the juvenile mafic arc crust is the mechanism for the origin of isotopically depleted granitoids in southern Tibet. It is this process that leads to differentiation of the juvenile mafic arc crust toward the felsic lithology in the continental arc. In this regard, the granitoids with depleted radiogenic isotope compositions do not necessarily contribute to the crustal growth at convergent plate boundaries.