Granites associated with hydrothermal uranium deposits provide critical insights into the processes governing uranium enrichment and mobilization within the continental crust. The Yangjiaonao deposit, situated in the Lujing ore field within the Nanling Metallogenic Belt (South China), is a typical granite-related hydrothermal vein-type uranium deposit. This study presents integrated zircon U-Pb geochronology, whole-rock geochemistry, whole-rock Nd isotopes and zircon Hf isotopes for the medium-to-coarse-grained porphyritic biotite (MCB) and medium-to-fine-grained two-mica (MFM) granites from the Yangjiaonao (YJN) granitic pluton. Both units yielded Triassic ages (~235–233 Ma), indicating synchronous emplacement during the Early Mesozoic period. However, they exhibit distinct metallogenic fertilities rooted in their petrogenesis. MCB granite, derived from greywacke-dominated sources, shows typical S-type characteristics, whereas uranium remained mineralogically sequestered in refractory accessory phases (e.g., zircon, monazite) during differentiation, evidenced by high and stable Th/U ratios. Conversely, MFM granite represents L-type peraluminous systems originated from felsic, arkose-like protoliths. Advanced fractionation in the MFM system triggered significant Th-U decoupling, driving Th/U ratios down to ~0.5 and promoting uranium enrichment in the residual melt. This differentiation-driven concentration of ‘leachable’ uranium identifies MFM granite as the primary fertile source for the Yangjiaonao hydrothermal mineralization.