Objective To explore the relationships between academic stress，sleep quality，meaning in life and depression in medical students and its mechanism so as to provide reference for medical students to prevent depression. Methods A total of 923 medical students were enrolled in the survey using Adolescent Self ⁃Rating Life Events Checklist（ASLEC），Patient Health Questionnaire⁃9（PHQ⁃9），Pittsburgh Sleep Quality Index（PSQI） and Personal Meaning Profile Brief（PMP⁃B）. Results The depression of medical students was positively correlated with academic stress and sleep quality（r = 0.42，0.53，P < 0.01）and negatively with meaning in life（r = -0.41， P < 0.01）. Sleep quality plays a mediating role between academic stress and depression. Meaning in life regulated the predictive effect of academic stress on sleep quality，for the effect of academic stress on sleep quality of medical students with low level of the meaning in life was more obvious. Conclusion Academic stress is a risk factor for depression in medical students，and sleep quality plays a mediating role in the process. As a positive psychological resource，the meaning in life can buffer the effect of academic stress on sleep quality，and then reduce the occur⁃ rence of depression in medical students.