Objective: To investigate the protective effect of melatonin (MT) on oxidative stress of hippocampal neurons in schizophrenic rats. Methods: 36 male SD rats were divided into 3 groups: control group, model group and model +MT group (10mg/kg), with 12 rats in each group. The rat model of schizophrenia was established by intraperitoneal injection of MK-801. After successful modeling, the model +MT group was intraperitoneally injected with MT, while the control group and the model group were injected with the same dose of 10% alcohol for 14 days. Morris water maze experiment was used to detect the learning and memory function of rats. Primary hippocampal cells were cultured by disconnection. The contents of ROS, SOD and MDA related factors in the culture medium of hippocampal cells were detected by kit method, and the number of apoptosis of hippocampal neurons was detected by TUNEL method. Results: Compared with the control group, the learning and memory function of the rats in the model group was impaired, the contents of ROS and MDA in the hippocampus were significantly increased, SOD activity was decreased, and the number of apoptotic neurons was significantly increased (P < 0.05).Compared with the model group, the learning and memory functions of the rats in the model +MT group were significantly improved, the contents of ROS and MDA in the hippocampus were decreased, SOD activity was increased, and the number of apoptotic neurons was significantly decreased (P<0.05). Conclusion: MT can significantly reduce the oxidative stress response and protect the neurons in the hippocampus of schizophrenic rats.