It is widely acknowledged that clay minerals have detrimental effects on the process of flotation, but the mechanisms involved are still not fully understood. In this work, the effects of montmorillonite, kaolinite, and illite on pyrite flotation were investigated from the perspective of various structures of clay minerals. Flotation tests suggested that the detrimental effect of clay minerals on the flotation of pyrite increased as follows: montmorillonite > kaolinite > illite. With the help of rheology measurements, it was found that montmorillonite significantly increased pulp viscosity, which in turn substantially reduced pyrite recovery and grade. Scanning electron microscopy (SEM) images suggested that montmorillonite formed the "house-of-cards" structure by edge-to-edge and edge-to-face contact, while kaolinite and illite platelets were associated mainly in the face-to-face mode. In addition, it was clearly observed by SEM-energy dispersive spectrometry that montmorillonite and kaolinite coat on the pyrite surfaces, which would lower the surface hydrophobicity of pyrite. Kaolinite covered much larger area of pyrite surface than montmorillonite owing to the positive charge occurring at the exposed aluminum-oxygen octahedral sheet of kaolinite. Although illite has a similar 2:1 structure to montmorillonite, it showed little or no effect on pyrite flotation, which was attributed to its poor swelling nature. These findings shed light on the root cause of the adverse effect of clay minerals on pyrite flotation and are expected to provide theoretical guidance for mitigating the negative effects on flotation caused by clays.