Modern sedentary lifestyle with altered dietary habits imposes the risk of human health towards several metabolic disorders such as obesity. The metabolic insults negatively affect the mental health status and quality life of affected individuals. Melatonin is a potent antioxidant with anti-inflammatory and neuroprotective properties. The aim of the present study was to investigate the protective effect of melatonin on the cognitive and neurochemical deficits induced by the high-fat diet (HFD) and alcohol (ALC) alone or in combination (HFD + ALC) in rats. Male Wistar rats were given ALC (3–15% i.e. increased gradually) and HFD for 12 weeks in different experimental groups. After 12 weeks, we found that simultaneous consumption of HFD and ALC exacerbates cognitive dysfunction and neurochemical anomalies. However, melatonin (10 mg/kg/day, i.p.) treatment for four weeks significantly prevented memory deficits, oxidative stress and neuroinflammation in HFD, ALC and HFD + ALC groups. RT-PCR analysis showed down-regulation of nuclear factor erythroid 2–related factor 2 (Nrf-2) and heme oxygenase-1 (HO-1) in ALC and HFD + ALC groups. Moreover, caspase-3 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) mRNA expression level were found up-regulated in hippocampus of HFD, ALC and HFD + ALC groups. However, calpain expression was found up-regulated only in the hippocampus of HFD + ALC group. Chronic treatment with melatonin significantly restored the aberrant gene expression level in HFD, ALC and HFD + ALC group. In conclusion, our findings indicated that melatonin can mitigate the HFD and ALC-induced cognitive deficits via attenuation of oxidative stress and calpain-1 dependent as well as independent caspase-3 mediated neuronal cell death.