Sandstone pore-plugging is a serious problem that bothers acid in situ leaching (ISL) uranium deposit, but currently, the mechanism of pore-plugging has not attracted much attention. In this study, using X-ray fluorescence, scanning electron microscope, optical microscope, and X-ray diffraction, we present both macro- and micro-evidence of pore-plugging occurred during acid in situ mining of sandstone uranium deposit at Yili Basin, NW (northwest) China. Our study reveals that in comparison with normal sandstones, the plugged sandstones are yellow in color and have relatively high contents of Fe and chamosite. The plugging in studied samples is mainly caused by precipitation of Fe(OH)3 at a pH of 2.0–4.0 for quantitative effect and by precipitation of gypsum (CaSO4·2H2O) as well. Alteration/dissolution of chamosite and to a lesser extent, Fe-bearing microcline and muscovite, may have contributed iron for Fe(OH)3 precipitation. It is suggested that adjustment of injection pH < 2.0 throughout the leaching passage would be an effective way to avoid/minimize this type of sandstone pore-plugging.