The capacity of Crassocephalum rubens (Juss Ex Jacq) leaf to protect against systemic oxidative stress was evaluated in N‐methyl‐N‐nitrosourea (MNU) – intoxicated rats fed at various inclusion rates for a period of twelve (12) weeks. Major organs and tissues were then assessed for indices of lipid peroxidation and oxidative stress. Crassocephalum rubens leaf significantly (p < .05) sustained the activities of superoxide dismutase and catalase with significant decrease in lipid peroxidation in MNU‐intoxicated animals, particularly at 5% and 10% inlusion rates. The dietary inclusion also prevented significant changes in hematological parameters such as neutrophil and lymphocyte counts. It also reduced the severity of histologic damages such as necrosis, epithelial degeneration, inflammatory cell infiltration and other pathological changes to major organs. These results indicate that regular consumption of C. rubens leaf, prevents the deleterious biologic effects of the damaging reactive oxidative species (ROS). Practical applications Crassocephalum rubens leaf has potential for development into a nutraceutical or functional food for chemoprevention and management of neurodegenerative diseases and other diseases associated with systemic oxidative stress, This is because its inclusion in the diet has attenuated lipid peroxidation, sustained the activity of antioxidant enzymes and mitigated deleterious changes in blood composition and tissue architecture resulting from exposure to a chemical carcinogen.