The feasibility of extracting uranium from natural ores has been studied, using supercritical CO2 and either commercial extractants (PC88A, Cyanex 301®) or an amidophosphonate molecule (named DEHCNPB). The impact of the process parameters has been evaluated. The uranium extraction yield was optimal at the lowest temperature (40 °C) and highest pressure (25 MPa) tested here. For a given CO2 flow rate, a compromise should be established between the amounts of extractant, acid and oxidant used. Uranium was successfully extracted directly from natural ore using DEHCNPB with a good selectivity over metal impurities such as iron, titanium and vanadium and yields up to 97%. Moreover, using Fe2(SO4)3 as an oxidant allows to minimize the water usage of the process. The mechanism of extraction using supercritical CO2 has been elucidated thanks to electrospray ionization mass spectrometry.