In order to identify promising radioprotector candidates, a series of benzyl sulfoxide/sulfone coumarin derivatives were designed and synthesized based on the reported activity of Ex-Rad. Most of the target compounds demonstrated significant radioprotective effects at concentrations of 40 μmol/L and 20 μmol/L in HUVECs. Among them, compounds 5q and 5u displayed superior activity in mitigating DNA damage compared with Ex-RAD. Notably, compound 5u significantly enhanced the viability of mice exposed to a lethal dose of ionizing radiation. In summary, the above findings suggested that compound 5u might be a promising radioprotective agent deserving further investigation.