In recent years, single‐atom catalysts (SACs) with separated active centers and high atom utilization have grown significantly as a significant area of catalytic research. In catalytic applications, SACs of various kinds have demonstrated exceptional performance, so the study of the catalytic mechanism of SACs provides a clearer direction for the preparation of catalysts with high performance. Strong linkages between the single atoms and the support are necessary to overcome the tendency of single atoms to aggregate into clusters, which is called metal‐support interaction (MSI). MSI affects not only the stability of individual atoms, but also the nature of the binding site and applicable reactions. Therefore, investigating the connection between MSI and the catalytic mechanism is crucial. This work describes the latest developments in the means of MSI and activity modulation in single‐atom catalysis. First, the synthesis strategies of SACs are presented, including ALD, co‐deposition, impregnation, and so on. Second, the catalytic mechanisms realized by using MSI in the loading of SACs with different types of supports are highlighted. Third, the strategies for the modulation of single‐atom catalytic activity are discussed, including heterojunction strategy, ligand environment strategy, and dual‐single‐atom strategy. Finally, possible directions for future development in single‐atom catalysis are suggested.