Uranium (U) is both chemically toxic and radioactive. Uranium mill tailings (UMTs) are one of the most important sources of U contamination in the environment, wherein the mechanisms that control U release from UMTs with different granularities have not yet been well understood. Herein, the release behaviours and underlying release mechanisms of U from UMTs with five different particle size fractions (<0.45, 0.45–0.9, 0.9–2, 2–6 and 6–10 mm) were studied with a well-defined leaching test (ANS 16.1) combined with geochemical and mineralogical characterizations. The results showed that the most remarkable U release unexpectedly emerged from UMT2–6 mm; in contrast, the smallest particle size UMT<0.45 mm contributed to the least U release. The predominant mechanism of U release from UMT2–6 mm was the oxidative dissolution of U-bearing sulfides, while abundant gypsum present in UMT<0.45 mm inhibited U release. The study highlights the importance of combined geochemical and mineralogical investigation when performing leaching tests of mineral-containing hazardous materials such as UMTs with consideration of particle size effects. The findings also indicate that elevating the content of gypsum and avoiding the oxidation of sulfides can effectively help immobilize and minimize the residual U release from the UMTs.