Background: The herb feverfew (Tanacetum parthenium L., Asteraceae) has an ancient reputation as an effective anti-inflammatory, analgesic, antipyretic, and anti-asthmatic agent. Parthenolide a gemacranolide-type sesquiterpene lactone is the major constituent of European feverfew. Materials and Methods: The present study was intended to evaluate the in vivo antioxidant potential and radioprotective ability of  Tanacetum parthenium leaf extract and synthetic Parthenolide. Male mice were orally administered with Tanacetum parthenium leaf extract and synthetic Parthenolide for 15 days followed by electron beam irradiation exposure. Survival studies in mice exposed to a lethal dose of 10Gy. At 6.0 Gy radioprotective ability was performed in order to find the nature of the compound. Results: The mice liver supernatant was used to measure total antioxidant capacity(TAC), glutathione (GSH) content along with various antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT) after electron irradiation exposure at 6.0 Gy. Pretreatment with Tanacetum parthenium extract and synthetic Parthenolide, prior to electron beam irradiation resulted in the increased survival rate of the animals as compared to the irradiated group. The treatment groups followed by electron beam irradiation at 6 Gy were significantly higher than the controlled group and the irradiated group, showing immunomodulatory nature. Pre-treatment and post-treatment with Tanacetum parthenium extract and synthetic Parthenolide, also significantly enhanced the activity of antioxidant enzymes and improved hematological parameters. Conclusion: The present study suggests that supplementation with leaf extract of Tanacetum parthenium and synthetic compound parthenolide has potent antioxidant activity and act as a probable radioprotector against electron beam radiation-induced oxidative damage.