Chemotherapy remains an important approach in the fight against malaria. Artemether–lumefantrine combination is widely in use due to its effectiveness against Plasmodium falciparum. Misuse in the form of multiple repeated doses of this anti-malaria drug is rampant in Nigeria. This study was designed to assess the hepatotoxic and clastogenic potential of extreme misuse of artemether–lumefantrine in rats. Graded doses of artemether–lumefantrine (1–5 mg/kg body weight) were administered by oral gavage for 6 weeks, twice daily, for 3 consecutive days per week. Artemether–lumefantrine, at all doses, did not have significant effects on the body and relative liver weight of treated group compared to the negative control group. The mean γ-glutamyltransferase, alanine, and aspartate aminotransaminase activity in groups of artemether–lumefantrine treated rats were significantly higher (p < 0.05) than that of the negative control group indicating that repeated administration of artemether–lumefantrine may be hepatotoxic. Findings from histological analyses of liver cross-section support the enzyme pattern of hepatoxicity. In addition, the drug, at all experimental doses, significantly induced (p < 0.05) formation of micronucleated polychromatic erythrocytes in the bone marrow cells of the treated rats compared with the negative control indicating clastogenic potential of the drug when misused. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 301–307, 2015.