In this work, a series of novel benzyl naphthyl sulfoxides (sulfones) derived from Ex-RAD were designed and synthesized as potential radioprotective agents. Some of the compounds considerably protected HUVECs against ⁶⁰Co γ-irradiation, accompanied by the absence of cytotoxicity. Compared to Ex-RAD, compound 8n not only exhibited a significant protective effect on cell survival and radiation-induced DNA damage, but also remarkably enhanced the survival (100%) of mice in 30 days after being exposed to irradiation. The results suggested that some target compounds are valuable for further research as promising radioprotectors.