Organic-rich shale related uranium (U) mineralization has attracted widespread attention as a strategic and clean alternative to fossil energy and a paleoceanic redox proxy. A comprehensive study of mineralogy, organic geochemistry and elemental geochemistry of the lower Cambrian Niutitang Formation organic-rich shales in northeastern Guizhou, South China was conducted to address this issue. SEM-EDS results showed that the U occurrence state in the Niutitang Formation shales is dominated by nanoscale U minerals, mainly including coffinite, brannerite, U-bearing apatite and U-bearing xenotime. Various states of U are closely associated with organic matter, apatite, pyrite and clay minerals. Based on geochemical indexes, paleomarine condition and event deposition jointly drove the U enrichment in the Niutitang shales, in which hydrothermal activities and/or volcanic eruptions increased U fluxes in seawater and euxinic environment with high primary productivity provided a favorable condition for U reduction. The adsorption, complexation and reduction of UO22+ by organic matter and the formation of uranyl phosphate complexes by the combination of phosphate and UO22+ accelerated U immobilization and enrichment from bottom water to sediments. The microbial activities (e.g., BSR) in this process created favorable euxinic conditions and released inorganic-phase P to provide available ligands for UO22+. The U enrichment models of the lower Cambrian Niutitang shales in northeastern Guizhou were established. This paper provides a new insight into the U enrichment mechanism in organic-rich shales, and may also have implications for the applicability of U as redox proxy and the exploration of organic-rich shale related U deposits.