Light, strong, and radiation-tolerant materials are essential for advanced nuclear systems and aerospace applications. However, the comprehensive properties of current radiation-tolerant materials are far from being satisfactory in harsh operating environments. In this study, a high-throughput-designed NbVTaSi refractory eutectic medium entropy alloy realizes the controllable formation of the β-Nb5Si3 phase with a high content and has outstanding comprehensive properties, i.e., lightweight, high yield strengths at room temperature and 850°C, and excellent He-ion irradiation resistance. According to density functional theory calculations and experimental findings, the prefabricated lattice distortion of the Nb50V42Ta8 phase leads to great phase stability under severe He-ion irradiation conditions, while the dual characteristics of the semi-coherent interface and hyperstatic lattice structure of the high-content β-Nb5Si3 phase dominate its outstanding He-ion irradiation resistance. This study sheds light on the design strategy for comprehensive properties and development of future radiation-tolerant materials for advanced nuclear systems and aerospace applications.