Despite advances in radiation therapy (RT), radiation-induced cardiovascular disease remains a major cause of long-term morbidity and mortality in cancer survivors, increasing cardiovascular risk by 10-30% within 5-10 years after treatment. Excess reactive oxygen species (ROS) are major drivers of RT-induced endothelial injury and cardiovascular dysfunction, causing direct oxidative damage to DNA, lipids, and proteins and activating inflammatory pathways that sustain endothelial dysfunction. Targeting ROS-mediated injury, therefore, represents a promising strategy to mitigate the cardiovascular toxicity of radiation therapy. Fullerenes (C60) and their derivatives are potent antioxidants and are referred to as "free radical scavengers" because of their ability to readily interact with and neutralize free radicals. Despite promising reports of the antioxidant and anti-inflammatory activity of C60 fullerenes in recent years, translating C60 into clinic application is challenging due to their inherent lipophilicity and insolubility in aqueous media. To address this challenge, we have developed a novel chemistry for the custom synthesis of C60 derivatized with serinol (C60-ser). This derivative is neutral, amphiphilic and exquisitely soluble in water. Our data demonstrated that C60-ser is non-toxic and can protect non-malignant normal endothelial cells, but not cancer cells, from RT-mediated damage. Mechanistically, C60-ser radioprotection is exerted by both neutralizing RT-induced free radicals and inducing antioxidant response pathway and activity of antioxidant enzymes to neutralize RT-induced free radicals. The resultant radioprotective effects include preservation of mitochondrial respiratory capacity and reduction in DNA damage, senescence, and inflammatory responses of endothelial cells, which together enhance the long-term cell survival after RT. Remarkably, C60-ser treatment upregulates the expression of the transcription factor Nrf2 and promotes its nuclear translocation, thereby activating the Nrf2-antioxidant response element (ARE) signaling axis for the expression of downstream antioxidant enzymes (catalase, SOD2, HO-1, NQO1, and TRX1) in normal cells but not in cancer cells. Collectively, these results highlight a critical role of the Nrf2-ARE pathway in mediating the effects of C60-ser against oxidative stress. This study advances the realization of the clinical translation of C60-ser for reducing RT-induced toxicity in cardiovascular tissues of cancer patients.