Introduction: Antipsychotic drugs are the main therapy for schizophrenia and have been widely used in mental disorder fields. However, the research on the safety of antipsychotic drugs in the real-world is rare. The purpose of this research is to evaluate the safety of antipsychotic drugs based on real-world data. Methods: ADR reports collected by the Henan Adverse Drug Reaction Monitoring Center from 2016 to 2020 were analyzed. We described the safety of antipsychotic drugs by descriptive analysis and four signal mining methods. Meanwhile, the risk factors for serious adverse reactions of antipsychotics were identified. Results: A total of 3363 ADR reports related to antipsychotics were included. We found that the number of adverse drug reaction reports and the proportion of serious adverse reactions have increased year by year from 2016 to 2020. Most adverse drug reactions occurred within 3 months after taking the medicine. The symptoms caused by typical antipsychotics and atypical antipsychotics were different and dyskinesia was more common in typical antipsychotics. Most patients improved or recovered after treatment or intervention while only one patient had sequelae. Low-level hospitals, psychiatric hospitals, youth, and old age could increase the risk of serious adverse reactions. Four off-label signals were found through signal mining, including amisulpride-pollakiuria, ziprasidone-dyspnoea, quetiapine-urinary incontinence, olanzapine-hepatic function abnormal. Conclusion: We found that most ADRs occurred within 3 months after taking the medicine, so close observation was required for patients during the first 3 months of treatment. The ADRs of antipsychotics involved multiple organ-system damages but were not serious. It might be recommended to take alternative drugs after a serious ADR occurred. The symptoms caused by typical APDs and atypical APDs were different. For patients with typical APDs, dyskinesia was more common and should be given special attention. Statistics showed that low-level hospitals, psychiatric hospitals, youth, and old age were risk factors for serious ADRs. The four off-label signals obtained by signal mining should be paid special attention, including amisulpride-pollakiuria, ziprasidone-dyspnoea, quetiapine-urinary incontinence, and olanzapine-hepatic function abnormal.