The work aims to study the effect of the structure and the size of MoS2 on its macro tribological properties and the sliding mechanism. The flower-like MoS2 microspheres of different sizes were synthesized by hydrothermal method and compared with the purchased commercial bulk MoS2 and single-layer MoS2. Four kinds of MoS2 powder were dispersed in ethanol, and four MoS2 coatings were prepared on the silicon wafer by spraying. Scanning electron microscope (SEM), X-ray diffraction (XRD), and transmission electron microscope (TEM) were used to characterize the morphology and structure of the powder and coatings. The tribological properties of the coatings were compared and studied. The morphology of the friction pair was observed by the optical microscopy. The SEM and TEM were used to study the structure and morphology of the friction interface. The four MoS2 samples were all composed of micro- or nano-sheets with the layered structure. The friction coefficients of the four materials were stable and less than 0.05. The wear life of bulk MoS2 was the shortest and the friction interface was covered by the less lubricating film. The single-layer MoS2 had a stable friction coefficient and the longest life. The friction interface was composed of numerous nanosheets and the friction process was mainly pure physical peeling. The life of the flower-like MoS2 microspheres was intermediate between those of bulk MoS2 and single-layer MoS2. The flower-like MoS2 microspheres were easy to be exfoliated under the action of friction force, and the exfoliated MoS2 nanosheets played an important role of lubrication during the friction process. The friction interface was covered with a thick and dense lubricant film. After the rubbing, the interlayer distance of flower-like MoS2 microspheres increased from 0.62 nm to 0.7 nm, which was conducive to good lubrication. The size can affect the sliding mechanism of MoS2, which significantly affects its wear life. The reduction of the layer and size is beneficial to improve the wear life.