Under the new development philosophy of carbon peaking and carbon neutrality, CO2 and O2 in situ leaching (ISL) has been identified as a promising technique for uranium mining in China, not only because it solves carbon dioxide utilization and sequestration, but it also alleviates the environmental burden. However, significant challenges exist in assessment of CO2 footprint and water-rock interactions, due to complex geochemical processes. Herein this study conducts a three-dimensional, multicomponent reactive transport model (RTM) of a field-scale CO2 and O2 ISL process at a typical sandstone-hosted uranium deposit in Songliao Basin, China. Numerical simulations are performed to provide new insight into quantitative interpretation of the greenhouse gas (CO2) footprint and environmental impact (SO42–) of the CO2 and O2 ISL, considering the potential chemical reaction network for uranium recovery at the field scale. RTM results demonstrate that the fate of the CO2 could be summarized as injected CO2 dissolution, dissolved CO2 mineralization and storage of CO2 as a gas phase during the CO2 and O2 ISL process. Furthermore, compared to acid ISL, CO2 and O2 ISL has a potentially smaller environmental footprint, with 20% of SO42– concentration in the aquifer. The findings improve our fundamental understanding of carbon utilization in a long-term CO2 and O2 ISL system and provide important environmental implications when considering complex geochemical processes.