BACKGROUND The aim of this study was to investigate whether melatonin is involved in brain injury following subarachnoid hemorrhage (SAH). MATERIAL AND METHODS An SAH model was established and TUNEL assays were utilized to detect the effect of melatonin on cell apoptosis. Western blot analysis was used to detect the effect of melatonin on expression of autophagic markers and apoptotic factors. Real-time PCR, Western blot analysis, and luciferase assay were performed to study the effect of melatonin on nuclear factor erythroid-2 related factor 2 (NRF2) expression. RESULTS The SAH group displayed a lower neurological score and a higher brain water content, while melatonin treatment increased the neurological score and decreased the brain water content. The administration of melatonin also inhibited the apoptosis of neurons in the brain. In addition, higher Beclin-1 expression and higher conversion ratio from LC3- II to LC3-I were observed in the SAH group. The activation of Beclin-1 and the conversion from LC3-II to LC3-I was further enhanced by melatonin treatment. Furthermore, in the SAH group, the level of Bcl-2 was decreased while the level of Bax and cleaved caspase-3 were increased. However, following melatonin treatment in the SAH group, the level of Bcl-2 was increased while the levels of Bax and cleaved caspase-3 were decreased. CONCLUSIONS Our study indicated that, by increasing the expression of NRF2, the mitophagy induced by melatonin provided protection against brain injury post-SAH.