Modifying the coordination or local environments of single‐, di‐, tri‐, and multi‐metal atom (SMA/DMA/TMA/MMA)‐based materials is one of the best strategies for increasing the catalytic activities, selectivity, and long‐term durability of these materials. Advanced sheet materials supported by metal atom‐based materials have become a critical topic in the fields of renewable energy conversion systems, storage devices, sensors, and biomedicine owing to the maximum atom utilization efficiency, precisely located metal centers, specific electron configurations, unique reactivity, and precise chemical tunability. Several sheet materials offer excellent support for metal atom‐based materials and are attractive for applications in energy, sensors, and medical research, such as in oxygen reduction, oxygen production, hydrogen generation, fuel production, selective chemical detection, and enzymatic reactions. The strong metal–metal and metal–carbon with metal–heteroatom (i.e., N, S, P, B, and O) bonds stabilize and optimize the electronic structures of the metal atoms due to strong interfacial interactions, yielding excellent catalytic activities. These materials provide excellent models for understanding the fundamental problems with multistep chemical reactions. This review summarizes the substrate structure‐activity relationship of metal atom‐based materials with different active sites based on experimental and theoretical data. Additionally, the new synthesis procedures, physicochemical characterizations, and energy and biomedical applications are discussed. Finally, the remaining challenges in developing efficient SMA/DMA/TMA/MMA‐based materials are presented.