Excessive alcohol consumption leads to neurodegeneration, driven primarily by oxidative stress and mitochondrial dysfunction, yet no specific treatment exists. Nicotinamide riboside chloride (NRC), a nicotinamide adenine dinucleotide precursor, has demonstrated therapeutic potential in mitigating mitochondrial dysfunction in heart failure, but its role in alcohol-induced neurodegeneration remains unexplored. This study investigated NRC’s neuroprotective effects using behavioral tests, serum ethanol and inflammatory marker analysis, hematoxylin-eosin staining, and molecular assays of in vitro models. Proteomics and GEO database analysis further elucidated the mechanisms of alcohol-induced brain injury. Results showed that NRC significantly improved alcohol-related cognitive impairment and neuroinflammation. Both our experimental data and external datasets identified mitochondrial dysfunction as a key driver of alcohol-induced neuronal damage, characterized by impaired mitophagy and disrupted mitochondrial unfolded protein response (UPR^mt). NRC supplementation restored mitochondrial homeostasis by enhancing UPR^mt and Fundc1-dependent mitophagy. Mechanistically, UPR^mt inhibition abolished NRC’s protective effects by suppressing Fundc1 expression and mitophagy, whereas mitophagy inhibition did not affect UPR^mt, suggesting a hierarchical regulation where UPR^mt governs Fundc1-mediated mitophagy. In conclusion, alcohol disrupts mitochondrial quality control, but NRC counteracts neuronal toxicity by activating UPR^mt and restoring Fundc1-driven mitophagy, offering a promising therapeutic strategy for alcohol-related neuronal damage.