Aflatoxin B1 (AFB₁) is a mycotoxin synthesised as a secondary metabolite by members of the Aspergillus species contaminating agricultural produce. Aspergillus species thrive in tropical climes, endemic to malaria. Artemisinin-based combination therapies (ACTs) effectively treat and prevent malaria recrudescence; Coartem (COA) is an ACT whose toxicity is evident. Although there are scanty studies on COA toxicity, the scientific literature is replete on AFB₁ toxic effects -including carcinogenicity. The current research investigates AFB₁ and COA toxicity in experimental Wistar rats' hepatorenal systems. Thirty albino rats were randomly grouped into five cohorts (n = 6) and treated as follows: Group I: Untreated control (2 mL/kg of corn oil); group II: AFB₁ alone (70 μg/kg); group III: COA alone (5 mg/kg); group IV: COA and a low dose of AFB1₁ (5 mg/kg & 35 μg/kg); while Group V: COA and a high dose AFB1₂ (5 mg/kg & 70 μg/kg) by gavage. Our results show that exposure to AFB₁ and COA significantly (p < 0.05) reduced superoxide dismutase, catalase, glutathione peroxidase, and glutathione-S-transferase activities, besides reduced glutathione and total sulfhydryl groups level. Reactive oxygen and nitrogen species, lipid peroxidation, 8-hydroxy-2′-deoxyguanosine, nitric oxide, xanthine oxidase, and myeloperoxidase levels were increased (p < 0.05) in rats co-treated with COA and AFB1. Cell death was aggravated in COA and AFB1 groups, exemplified by increased Caspase-3 and 9 activities and alterations in the typical histological features of experimental rats’ livers and kidneys. Finally, rats co-treated with AFB₁ and COA experienced increased hepatorenal dysregulation, oxidative and inflammatory tissue damage, and apoptotic cell death. All the observed systemic perturbations occurred dose-dependently. It is crucial, therefore, to prevent AFB₁ dietary contaminations during COA therapeutic regimen due to increased pathophysiological damage exerted on experimental rat liver and kidneys, as evidenced in this study.