The escalating utilization of ionizing radiation across medicine and industry underscored the paramount urgency of effective radioprotective materials. Conventional materials such as lead and concrete are widely used, and lead-free materials have also emerged to solve the problems of cumbersome and toxic lead, such as metal-containing micro/nano materials and polymers. Nevertheless, there is still a significant challenge in meeting the urgent need for lightweight and biocompatible alternatives. To tackle this challenge, this work utilizes molecular engineering of melanin to develop a panel of metal-free melanin materials with enhanced conjugation, heightened physical shielding against radiation and effective antioxidant properties. Furthermore, engineered melanin materials demonstrated in vivo γ-ray protection, increasing mice survival from ~12% to 100% after 6 Gy total body irradiation.© 2025. The Author(s).