Lightweight, strong, and radiation-tolerant materials are essential for advanced nuclear systems and aerospace applications. However, the current research for these materials mainly focuses on a single design strategy to improve their irradiation resistance via empirical trial-and-error learning. In this study, a novel NbVTaSi refractory eutectic high-entropy alloy was target designed via high-throughput thermodynamic calculations. To exploit the unique eutectic structures of NbVTa and β-Nb5Si3 phases, a new synergistic mechanism for irradiation resistance via balancing inhibition effects on the generation of He-induced lattice defects and the formation and growth of He bubbles was proposed according to the experimental findings and density functional theory calculations. The alloy possesses lightweight (7.4 g/cm3), high yield strengths at room temperature (2.60 GPa) and 850 ℃ (1.84 GPa), and outstanding He-irradiation resistance, superior to other reported radiation-resistant alloys. This study sheds light on the development of future radiation-tolerant materials for advanced nuclear systems and aerospace applications.