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This study explores the mediating role of mentalization—the psychological capacity to understand the mental states of oneself and others—in the relationship between academic stress and depressive symptoms among university students during the COVID-19 pandemic. Conducted in Valparaíso, Chile, with a sample of 300 students, the study utilizes a cross-sectional design. Depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9), stress levels were measured with the Depression Anxiety Stress Scales-21 (DASS-21), and mentalization was evaluated through the Reflective Functioning Questionnaire. Results reveal that disruptions in mentalization, specifically uncertainty about mental states, partially mediate the impact of stress on depressive symptoms, highlighting the crucial role of mentalization processes in the development and management of depressive symptoms under stressful conditions. The findings emphasize the importance of enhancing mentalization capabilities in university settings to improve students' resilience to stress, particularly in crisis situations like the pandemic. This research underscores the necessity of integrating mentalization-focused strategies in preventive and therapeutic interventions for university students to support their mental health and well-being.