INTRODUCTION: Intracranial aneurysms (IAs) are relatively common cerebrovascular anomalies. Melatonin could modulate inflammatory and offers neuroprotective effects, and its role in IA has not been fully elucidated. METHODS: An elastase-induced IA mouse model was constructed and melatonin (150 mg/kg) was administered to investigate its therapeutic effects on IA. Aneurysm formation was observed by bromophenol blue gelatin perfusion, and the pathology changes in IA mice were examined using hematoxylin-eosin (HE) staining. The potential mechanisms of melatonin treatment of IA were explored using western blot, enzyme-linked immunosorbent, real-time qPCR, immunohistochemistry, and flow cytometry. An H RESULTS: The formation of aneurysms was observed in the circle of Willis in the IA mice. Melatonin treatment alleviated the thinning of blood vessel walls and disruption of the internal elastic lamina in IA mice. The levels of Bcl-2 were significantly increased and Bax and cleaved caspase-3 were decreased in IA mice with melatonin treatment, suggesting reduced apoptosis. Furthermore, melatonin reduced levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) in IA mice. The H CONCLUSION: Melatonin mitigates IA injury by modulating immune cells and hypoxia-related factors. These findings provide an exploratory foundation for therapeutic strategies in IA.