Abstract:  Melatonin‐selenium nanoparticles (MT‐Se), a novel complex, were synthesized by preparing selenium nanoparticles in melatonin medium. The present investigation was designed to determine the protective effects of MT‐Se against Bacillus Calmette–Guérin (BCG)/lipopolysaccharide (LPS)‐induced hepatic injury in mice. In BCG/LPS‐induced hepatic injury model, MT‐Se administered (i.g.) at doses of 5, 10, or 20 mg/kg to BCG/LPS‐treated mice for 10 days, significantly reduced the increase in plasma aminotransferase, reduced the severe extent of hepatic cell damage and the immigration of inflammatory cells. The MT‐Se particles also attenuated the increase in the content of thiobarbituric acid‐reactive substances and enhanced the decrease in reduced activities of superoxide dismutase and glutathione peroxidase (GPx). However, treatment with MT‐Se suppressed the increase in nitric oxide levels both in plasma and liver tissue. Furthermore, supplementation with MT‐Se at the dose of 10 mg/kg (composed of 9.9 mg/kg melatonin and 0.1 mg/kg selenium) had great capability to protect against hepatocellular damage than a similar dose of melatonin (10 mg/kg) or selenium (0.1 mg/kg) alone. This effect may relate to its higher antioxidant efficacy in decreasing lipid peroxidation and increasing GPx activity. These results suggest that the mode of MT‐Se hepatic protective action is, at least in part, related to its antioxidant properties.