Mental health problems are frequent obstacles in medical students’ careers as doctors. Given that previous studies overlook the mediation of stress perception, the current study expanded previous goal orientation researches by addressing an unexplored mechanism. This study aims to examine the mediational roles of stress perception on the relationship between achievement goal orientation and depression in medical students. A total of 1,015 Chinese 2-year medical students completed a multi-section questionnaire. Hypotheses were examined by structural equation modeling. The findings suggest that (...) performance-avoidance goal orientation and perceived stressors both demonstrated direct facilitative effects on depression, whereas stress-related cognition demonstrated direct obstructive effects on depression. Both perceived stressors and stress-related cognition mediated the relationship between achievement goal orientation and depression. The findings spark a new perspective on motivational intervention that assist students in adopting mastery-approaching strategy as well as ways of coping with stressful academic situations. Identifying students with achievement goal orientation and providing them with the appropriate supportive services may help them to manage stress and mitigate or prevent depression. (shrink)