The Daliang deposit in the Motianling area of South China is unique for its synchronous uranium mineralization with regional metamorphism. To elucidate its genetic mechanism, whole-rock geochemistry from the Daliang deposit was undertaken, along with analyses of the chemical and isotopic signatures of minerals. The Motianling granitoids exhibit strongly peraluminous S-type affinities with low Th/U ratios, representing a uranium source for mineralization. Altered mineralogical and geochemical signatures of altered and ore samples indicate a multistage history after granitic emplacement: (1) Late magmatic-hydrothermal alteration characterized by greisenization, K-feldspathization, and propylitization; and (2) brittle-ductile deformation with uranium mineralization. Notably, ore-stage alteration mineral contains chlorite + quartz + sericite, which is consistent with the mineral assemblage of low-greenschist facies metamorphism. EMPA and LA-ICPMS dating on pitchblende yielded ages of 378 and 380 Ma, coinciding with the timing of regional ductile deformation. The pitchblende exhibits weak fractionation between LREEs and HREEs and negative Eu anomalies, mirroring characteristics observed in syn-metamorphic uranium deposits. Therefore, we suggest that uranium mineralization within the Daliang was related to crustal metamorphism, and the Daliang deposit belongs to syn-metamorphic deposit. Fluids likely have been liberated from the acidic brines-bearing Sibao Group that underwent low-greenschist facies metamorphism. Paleozoic intracontinental orogeny in South China resulted in brittle-ductile deformation in the Motianling pluton. These zones provided favorable pathways for the migration of ore-forming fluids and subsequent uranium mineralization. Late Devonian retro-metamorphism facilitated the percolation of oxidizing metamorphic fluids into the Motianling granitoids, circulating along the pre-existing brittle-ductile zones. This study presents the first evidence for syn-metamorphic uranium deposits within the granite of South China. This finding suggests potentially distinct mineralization mechanisms compared to traditional granite-related uranium deposits in the region, warranting further investigation.