The Mengqiguer deposit in the southern Yili basin Ili Basin is a large interlayer-oxidation-zone type uranium deposit. In this paper, we applied multiple methods including microscopic observation, scanning electron microscope and electronic probe, to analyze the systematical alteration characteristics of the ore-bearing sandstone layer. Fluid inclusion and stable isotope studies on the ore-bearing sandstone have also been carried out to discuss the internal relations between fluid activities, epigenetic alteration and the uranium mineralization. Major epigenetic alteration include clay alteration, carbonatization and pyritization, of which biogenetic pyritization is most closely related to the uranium mineralization. This suggests the existence of microorganism during the uranium mineralization process. The mineralization fluids of low temperature, medium density but varied salinities are suggested to be derived from multi-source, including the meteoric water and organic acidic vapor components from coal-bearing strata. Uranium mineralization, grain-dispersed kaolinite, limonite, colloidal pyrite, and the carbonate cements associated with sulfate-reducing bacteria were formed by meteoric water and vermicular-shaped kaolinite, autologous pyrite, and the carbonate cementation associated with the dehydroxylation of organic matter was formed by organic acidic. Based on these results, we consider that the uranium mineralization and epigenetic alteration both resulted from the reciprocity of organic–inorganic fluid and fluid–rock during the formation of the interlayer oxidation zone.