This study examines the role of salient external factors (family, peer and school caring relations) and internal factors (goals and aspirations, problem solving and self-efficacy, empathy, and self-awareness) in protecting adolescents experiencing interpersonal problems and academic pressure from depression. A total of 1,297 eighth and ninth grade students in Shandong province of Eastern China completed self-report measures. Results of hierarchical regression analyses indicated that interpersonal problems and academic pressure predicted depression positively. Peer caring relationships, home caring relationships, goals and aspirations, problem solving and self-efficacy, and self-awareness predicted depression negatively, but empathy did so positively. The interactions of home caring relationships with interpersonal problems, peer caring relationships with academic pressure, and self-awareness with academic pressure were negatively associated with depression. The relationships between interpersonal problems and depression, and academic pressure and depression, were less apparent for adolescents who had higher levels of peer caring relationships, home caring relationships, and self-awareness. The results suggest that school psychologists and counselors should note and build upon positive strengths while providing intervention services for adolescents experiencing depression related to interpersonal problems and academic pressure.