Single-atom catalysts (SACs), characterized by ultra-high atomic utilization, well-defined active sites, and theoretically maximal mass activity, have emerged as a rewarding frontier in heterogeneous catalysis. Given that on-demand, customizable, and scalable precise synthesis is essential for the practical deployment of SACs, multifarious, and structurally tunable metal–organic frameworks (MOFs) have thus become among the most prominent precursors for SAC synthesis. In this chapter, we provide a comprehensive review of recent advances in MOF-based SACs, including both SACs that directly utilize MOFs and those derived from MOFs. Classified by the metal elements at the single-atom centers, we review the existing synthesis methods for MOF-based SACs, thoroughly discussing the advantages and disadvantages of each method, as well as the key role that MOFs play in these processes. We also present the applications of MOF-based SACs in different catalytic reactions, with particular attention to the relationship between their structure and catalytic performance. Finally, we identify the challenges in the synthesis and applications of MOF-based SACs and propose potential solutions and future research directions.