BACKGROUND: Nursing and medical students are suffering from high rates of depressive symptoms. Mental health benefits students' learning, growth and professional development. Exploring psychological resources to prevent depression is emphasized recently, and self-compassion is shown to be inversely associated with depressive symptoms. However, the mechanism through which self-compassion contributes to decreased depressive symptoms is limited. Therefore, this study aimed to explore and examine a model detailing the potential paths between self-compassion and depressive symptoms. METHODS: A cross-sectional study was conducted and convenient sampling was used. Among the 1800 nursing and medical students targeted from two universities in East and North China, 1341 completed the questionnaires, and 1127 valid questionnaires were analyzed comprising 566 and 561 from medical and nursing students, respectively. Data in May 2020 and July 2020 were collected through Patient Health Questionnaire, self-compassion scale, resilience scale, Life Orientation Test and Perceived Stress Scale. Then, path model analysis was conducted to analyze the data. RESULTS: Finally, this study included 1125 valid questionnaires after excluding two extremes of study variables. Participants consisted of 50.2% medical students and 49.8% nursing students. The model showed an acceptable fit to the data. After controlling for the demographics, self-compassion was directly and indirectly associated with decreased depressive symptoms by increasing resilience and optimism and reducing perceived stress among nursing and medical students. Resilience and optimism were directly and indirectly associated with decreased depressive symptoms by reducing perceived stress among nursing students and indirectly associated with decreased depressive symptoms among medical students. CONCLUSIONS: The study provides evidence that self-compassion significantly influences the decrease in depressive symptoms by increasing resilience and optimism and reducing perceived stress. These findings suggested that programs enhancing students' self-compassion, resilience, and optimism simultaneously can help decrease depressive symptoms and improve mental health in education and healthcare institutes. These findings may facilitate the designing of educational programs for preventing depressive symptoms and promoting mental health among nursing and medical students.