Evidence abounds-epidemiological and experimental-linking overexposure to manganese with hepatic and renal dysfunction. We investigated the beneficial effects of gallic acid or omega-3 fatty acids (omega-3-FA) on hepatorenal function in rats exposed to manganese (Mn). Rats were exposed to manganese (15 mg/kg) only or in the presence of omega-3-FA (30 mg/kg) or gallic acid (20 mg/kg) continuously for 14 days. Gallic acid or omega-3-FA co-treatment significantly (P < 0.05) suppressed manganese-mediated increases in the biomarkers of hepatorenal toxicity. Furthermore, gallic acid or omega-3-FA relieved manganese-induced oxidative stress, lipid peroxidation, and glutathione depletion.In addition to decreases in nitric oxide, interleukin-1 beta, tumor necrosis factor-alpha levels, and myeloperoxidase concentration in treated rats, biochemical data on hepatorenal protection were buttressed by our histological findings. Gallic acid or omega-3-FA ameliorated manganese-induced hepatorenal toxicity by reducing the oxidative/inflammatory stress and preserved tissue integrity in rats. Impact statement Humans and animals are regularly exposed to toxic chemicals with subsequent adverse effects. Manganese exposure occurs via contaminated sources; over-exposure is associated with neuronal, hepatorenal dysfunction, etc. This work advances the field of natural chemopreventive agents by reporting evidence lacking in the literature on GA and omega-3-FA obtained primarily from the diet in protecting biological beings against toxic chemicals. Individually, GA and omega-3-FA exhibit various pharmacological effects. Our findings confirm the previous reports; however, we demonstrate the additional evidence for GA and omega-3-FA in abating toxic response incumbent on oxidative damage associated with manganese exposure. These findings further underscore the relevance of GA usage in food, cosmetics-pharmaceutical industries, and omega-3-FA as a safe supplement. Dietary supplements with GA and fish oil-rich in omega-3FA may be the potential natural therapy against hepatorenal injury in individuals inadvertently or occupationally exposed to manganese, thereby, promoting human and veterinary health outcomes.