Oxidative stress is a key factor in neuronal damage associated with Parkinson's disease. Previous studies have suggested that increased intake of purine-rich foods may improve the prognosis of patients with Parkinson's disease, although the underlying mechanism remains unclear. This study aims to demonstrate that hypoxanthine alleviates neuronal damage in Parkinson's disease and to explore the role of purine compensatory pathways. After 6 weeks of hypoxanthine intervention in an MPTP-induced Parkinson's disease animal model, the mice showed significant improvements in motor behavior, reduced oxidative stress damage in striatal neurons, and enhanced energy metabolism. Hypoxanthine was found to activate striatal purine compensation and stimulate the AMPK signaling pathway. Using an MPP⁺-induced SH-SY5Y cell model and si-hprt1 knockdown experiments, we further demonstrated that hypoxanthine ameliorates mitochondrial damage and inhibits apoptosis through the HPRT1-AMPK pathway. The clinical relevance of these findings is supported by a negative correlation between serum hypoxanthine and symptom severity. These findings identify hypoxanthine as a key bioactive nutrient with potential therapeutic value in Parkinson’s disease, acting through purine-mediated modulation of energy metabolism and oxidative stress.