In the quest of new materials that can withstand severe irradiation and mechanical extremes for advanced applications (e.g. fission reactors, fusion devices, space applications, etc), design, prediction and control of advanced materials beyond current material designs become a paramount goal. Here, though a combined experimental and simulation methodology, the design of a new nanocrystalline refractory high entropy alloy (RHEA) system is established. Compositions of this alloy, assessed under extreme environments and in situ electron-microscopy, revealed both high mechanical strength and thermal stability, grain refinement under heavy ion irradiation and outstanding irradiation resistance to dual-beam irradiation and helium implantation, marked by remarkable resistance to defect generation, growth and coalescence. The experimental and modeling results – which demonstrated notable agreement – can be applied to design and rapidly assess other alloys subjected to extreme environmental conditions.