Interface coupled dissolution-reprecipitation reactions (ICDR) are a common feature of fluid-rock interaction during crustal fluid flow. We tested the hypothesis that ICDR reactions can play a key role in scavenging minor elements by exploring the fate of U during the experimental sulfidation of hematite to chalcopyrite under hydrothermal conditions (220–300 °C). The experiments where U was added, either as solid UO2+x(s) or as a soluble uranyl complex, differed from the U-free experiments in that pyrite precipitated initially, before the onset of chalcopyrite precipitation. In addition, in UO2+x(s)-bearing experiments, enhanced hematite dissolution led to increased porosity and precipitation of pyrite+magnetite within the hematite core, whereas in uranyl nitrate-bearing experiments, abundant pyrite formed initially, before being replaced by chalcopyrite. Uranium scavenging was mainly associated with the early reaction stage (pyrite precipitation), resulting in a thin U-rich line marking the original hematite grain surface. This “line” consists of nanocrystals of UO2+x(s), based on chemical mapping and XANES spectroscopy. This study shows that the presence of minor components can affect the pathway of ICDR reactions. Reactions between U- and Cu-bearing fluids and hematite can explain the Cu-U association prominent in some iron oxide-copper-gold (IOCG) deposits.