The Guangshigou deposit is the largest pegmatite-type uranium deposit in the Shangdan domain of the North Qinling Orogenic Belt, which is characterized by the enrichment of uraninite hosted in biotite granitic pegmatites. At Guangshigou, uraninite commonly occurs as mineral inclusions in quartz, K-feldspar and biotite or in interstices of these rock-forming minerals with magmatic characteristics (e.g., U/Th < 100, high ThO2, Y2O3 and REE2O3 contents and low concentrations of CaO, FeO and SiO2). It crystallized at 407.6 ± 2.9 Ma from fractionated calc-alkaline high-K pegmatitic melts under conditions of 470–700 °C and 2.4–3.4 kbar as deduced by the compositions of coexisting peritectic biotite. The primary uranium mineralization took place during the Late Caledonian post-collisional extension in the North Qinling Orogen. After this magmatic event, uraninite has experienced multiple episodes of fluid-assisted metasomatism, which generated an alteration halo of mineral assemblages. The alteration halo (or radiohalo) was the result of the combined effects of metamictization and metasomatism characterized by an assemblage of goethite, coffinite and an unidentified aluminosilicate (probably clay minerals) around altered uraninite. This fluid-assisted alteration was concomitant with the albitization of K-feldspar subsequently followed by the coffinitization of uraninite during the major period of 84.9–143.6 Ma, as determined by U-Th-Pb chemical ages. Further investigations revealed that the metasomatic overprinting on uraninite initially and preferentially took place along microcracks or cavities induced by metamictization and promoted their amorphization, followed by the release of U and Pb from structure and the incorporation of K, Ca and Si from the fluids, finally resulting in various degrees of uraninite coffinitization. The released U and Pb were transported by alkali-rich, relatively oxidizing fluids and then re-precipitated locally as coffinite and an amorphous U-Pb-rich silicate under low to moderate temperature conditions (85–174 °C). The compositional changes in primary uraninite, its structure amorphization together with the paragenetic sequence of secondary phases, therefore, corroborate a combined result of intense metamictization of uraninite and an influx of alkali–metasomatic fluids during the Late Mesozoic Yanshanian magmatic event in the region. Hence, the remobilization and circulation of uranium in the North Qinling Orogen was most likely driven by post-Caledonian magmatism and hydrothermal activities related to large-scale tectonic events. In this regards, Paleozoic pegmatite-type uranium mineralization may represent a significant uranium source for Mesozoic hydrothermal mineralization identified in the Qinling Orogenic Belt.