Objective: To investigate the prevalence of depression of middle school students in Liaoning Province in 2019 and analyze its influencing factors, to provide corresponding strategies and measures for depression prevention and control. Methods: By using the method of multi-stage stratified random cluster sampling, the 32 909 students of grade 1-3 of junior middle school, senior high school and vocational high school were selected from 14 cities in Liaoning province, and were investigated with Center for Epidermiologic Studies Depression Scale (CES-D) psychological scale. Results: The depression score of middle school students in Liaoning Province was (12.66±9.53), and the incidence of depression was 19.5%. Analysis of variance and multiple regression analysis showed that the main factors influencing the occurrence of depression were grade, bullying on campus, internet addiction, being beaten and scolded by parents, drinking, gender, Leave of absence from school, smoking, serious injury and economic classification (P<0.05). Conclusion Depression of middle school students in Liaoning Province is not optimistic. Effective prevention and control measures should be developed and implemented to the occurrence of adverse factors, so as to reduce the occurrence of depression symptoms.