High-entropy alloys (HEAs) exhibit exceptional properties that often surpass those of conventional alloys, making them a promising focus of research for future structural and functional applications. Among these properties, thermal and radiation resistance are critical in extreme environments where conventional materials are prone to degradation and failure over time. This chapter offers a comprehensive overview of the thermal and radiation resistance of HEAs, integrating fundamental concepts with recent experimental findings and theoretical developments. It highlights key mechanisms contributing to their thermal and irradiation stability and discusses strategies for enhancing performance through compositional tuning, microstructural design, second-phase incorporation, and grain boundary engineering. Finally, the chapter outlines future research directions aimed at advancing both the fundamental understanding and practical implementation of HEAs in demanding environments.