Background: Alcohol-induced neurodegeneration, a consequence of chronic ethanol exposure, is a neuroadaptation that drives the progression of alcohol use disorder (AUD). Unfortunately, conventional drugs for AUDs do not prevent neurodegeneration as part of their pharmacological repertoire. Multimodal neuroprotective therapeutic agents are hypothesized to have high therapeutic utility in the treatment of central nervous system. Interestingly, nutraceuticals by nature are multimodal in mechanisms of action. Purpose: This study examined the neuroprotective potential of Jobelyn in prefrontal cortex (PFC) of a binge-alcohol rat model of AUD. Methods: Three groups of rats were fed thrice daily through an orogastric tube with 5 g/kg ethanol (25% w/v), 5 g/kg ethanol (25% w/v) plus Jobelyn (4 mg/kg body weight), and 5 g/kg of a nutritionally complete diet (50% v/v), respectively. Cytoarchitectural study of the PFC was done in slides stained with haematoxylin and eosin. Immunohistochemical analyses were performed with mice monoclonal anti-p53 and anti-neuron specific enolase (NSE) antibodies to detect the degree of apoptosis and necrosis in the PFC. In addition, the degree of tissue damage and the level of lipid peroxidation were evaluated. Results: Jobelyn supplementation significantly lowered the levels of histologic and biochemical indices of neurodegeneration, and caused an increased expression of p53 protein and a decreased expression of NSE immunoreactivity (NSE-IR). Conclusions: Jobelyn supplementation ameliorates neurodegeneration in the PFC of AUD rats by reducing the oxidative stress, reducing the NSE-IR, and by increasing the expression of cellular tumor antigen p53 in the cortical neurons.