Granitoids play a critical role in understanding the maturation and reworking of continental crust within collisional orogenic systems. However, the diverse origins of magma sources, combined with the intricate dynamics of tectonic processes, present significant challenges for deciphering the genesis and evolutionary history of granitic magmas, particularly in geologically complex regions such as the Gangdese belt, southern Tibet. Here, we investigate the granitic plutons of the Eocene (dated at ca. 53 Ma) and Oligocene (dated at ca. 29 Ma) epochs in the eastern Gangdese belt, southern Tibet. Utilizing a multipronged approach combining whole-rock and mineral geochemistry, Sr-Nd-Hf-O isotopes, geochronology, and thermodynamic modeling, we aim to evaluate their sources, evolution, and the related tectonic processes. The Eocene granodiorite exhibits flat rare earth element (REE) patterns with weak heavy-REE depletion, enrichment in large ion lithophile elements (LILEs), and depletion in high field strength elements (HFSEs). Its isotopic signatures ε_Nd(t) = +1.3 to +2.1; zircon ε_Hf(t) = +0.7 to +7.4; δ¹⁸O = 5.2‰−7.0‰; and Sr-Nd mixing models suggest that the Eocene granodiorite primarily originated from the juvenile lower crust with the assimilation of the Nyingchi ancient basement (∼10%). Thermodynamic modeling further indicates that the magma formed through disequilibrium partial melting of mafic lower crustal rocks, leaving a pyroxene-rich residue. In contrast, the Oligocene granites display distinct adakitic geochemical features, including elevated whole-rock (⁸⁷Sr/⁸⁶Sr)_i isotopic ratios (0.7060−0.7061), relatively enriched ε_Nd(t) values (−3.0 to +0.8), and broad δ¹⁸O values (4.5‰ to 8.3‰). The significant variation in zircon ε_Hf(t) values (+0.1 to +8.0) suggests a mixed source. Multiple lines of evidence suggest that the Oligocene granites were formed through fluid-fluxed melting of a thickened crust, with the involvement of ∼25% Indian continental materials. The trace element characteristics, combined with thermodynamic modeling, indicate that the Oligocene granites underwent limited fractional crystallization (∼15%), with amphibole, rutile, and garnet being the dominant phases segregated during magma ascent. Considering the regional geology and rock assemblages, we propose a detailed geodynamic framework for the formation of the Eocene and Oligocene granites in the Gangdese belt. This study provides new insights into the distinct magma sources and evolutionary pathways of Eocene and Oligocene granites, while also establishing a quantitative framework to constrain magma genesis in syn-collisional and postcollisional settings. These findings have broad implications for advancing our understanding of granite petrogenesis in continental collisional orogens on a global scale.