Objective: To examine the influence of school adaptation on depression among high school students, as well as the mediating effects of social avoidance and distress and learning burnout on the relationship between school adaptation and depression among high school students, so as to provide a basis for the mental health promotion among high school students. Methods: A convenience sampling method was used to select 1 207 first year high school students from two high schools as the research subjects in Guiyang City. The School Adaptation Scale(SAS), Social Avoidance and Distress Scale(SAD), Learning Burnout Questionnaire(LBQ), Patient Health Questionnaire-9(PHQ-9) were used to conduct surveys at three time points: October 2021 (T1), May 2022 (T2), and March 2023 (T3). Common method biase was tested using the Harman s single factor method,and bias correction was conducted via the Bootstrap method, utilizing 5 000 resamples to analyze the 95% confidence intervals(95% CI ) of parameter estimates. Results: School adaptation at T1 was negatively associated with depression of high school students at T3 ( β =-0.13, P <0.01). The mediation analysis showed that the mediating effect of social avoidance and distress at T2 between school adaptation at time point T1 and depression among high school students at time point T3 was-0.100 (95% CI =-0.134--0.071, P <0.05). The mediating effect of learning burnout at T2 between school adaptation at time point T1 and depression among high school students at time point T3 was-0.157 (95% CI =-0.211--0.106, P <0.05). The chain mediation effect of social avoidance and distress and learning burnout at T2 between school adaptation at time point T1 and depression among high school students at time point T3 was -0.022 (95% CI =-0.037--0.012, P <0.05). Conclusions Good school adaptation can directly alleviate depressive mood, and can indirectly reduce depression through social avoidance and distress and learning burnout among high school students. Families and schools should pay attention to the school adaptation of high school students and provide timely interventions and assistance to students with poor adaptation.