The capability of lophirones B and C to extenuate aflatoxin B1 (AFB1)-mediated onslaught on cellular proteins, lipids, and DNA was investigated for 6 weeks. Lophirones B and C significantly (P < 0.05) increase the expression and specific activity of cytoprotective enzymes (glutathione-S-trans-ferase, nioctinamide adenine dicludeotide:quinone oxidoreductase-1, epoxide hydrolase, and uridyl glucuronosyl transferase). There was significant (P < 0.05) reduction in the level of antioxidant system in AFB1-induced hepatocarcinogenesis. Furthermore, lophirones B and C significantly (P < 0.05) attenuated AFB1-mediated decrease in the specific activities of antioxidant enzymes. Oxidative stress biomarkers, malondialdehyde, lipid hydroperoxides, conjugated dienes, protein carbonyl, and fragmented DNA were significantly (P < 0.05) elevated in AFB1-treated rats. Although lophirones B and C did not significantly (P < 0.05) alter these biomarkers, an AFB1-mediated increase in these biomarkers was significantly attenuated. Results obtained showed that lophirones B and C extenuate AFB1-mediated onslaught on cellular proteins, lipids, and DNA by enhancing nuclear erythroid-related factor-2 expression.