Achieving synergetic improvements of mechanical strength, toughness, and thermal stability of epoxy resin has been a crucial but very challenging issue. Herein, to explore a new solution for circumventing this issue, polyimide microspheres were successfully prepared through the inverse nonaqueous emulsion process, and the structure, size distribution and morphologies of polyimide (PI) microspheres were comprehensively investigated. Then the PI microspheres were incorporated in epoxy resin matrix to systematically investigate the mechanical and thermal properties of obtained epoxy/PI microspheres composites. It was found that the PI microspheres can not only enhance the mechanical strength of epoxy resin, but also significantly improve the toughness. Specially, the epoxy‐based composites containing 3 wt% PI microspheres exhibit a 47% increase in tensile strength, while the GIC and Charpy impact strength increase by 106% and 200%, respectively. The toughing mechanism of epoxy/PI microspheres composites was discussed. Moreover, the PI microspheres can also endow the epoxy resin with excellent thermal stability and heat resistance. Thus, this work may open a new opportunity to synergistically enhance the mechanical and thermal properties of epoxy‐based composites and may also give some valuable inspiration for the rational design of other high‐performance thermosetting composites.