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Background Previous studies have indicated that depression is common among young adults. However, these studies have mainly focused on risk factors rather than protective factors, especially in the context of Vietnam. Aims To explore protective factors such as self-compassion and the mediating role of gratitude, crucial for informing targeted interventions aimed at reducing depression in this population. Method A cross-sectional study was conducted in September 2023 using convenience sampling of individuals aged 18–25 years ( n = 356, mean age 21.23 years) living in Ho Chi Minh City, Vietnam, recruited via online surveys distributed through social networks. The required sample size was determined using Monte Carlo power analysis to ensure adequate statistical power for mediation analysis. Data were analysed to examine the mediating role of gratitude (Gratitude Questionnaire – Six Item Form, GQ-6) in the relationship between self-compassion (Self-Compassion Scale – Short Form, VSCS-SF) and depression (Patient Health Questionnaire-9, PHQ-9). Results Self-compassion showed a significant negative association with depression ( β = −0.50, t = −11.42, p < 0.001), accounting for 27% of the variance in depression scores. Gratitude significantly mediated this relationship, with an indirect effect of a × b = −0.07 (s.e. = 0.02, 95% CI −0.11 to −0.04]). Specifically, self-compassion positively predicted gratitude ( β = 0.34, t = 6.80, p < 0.001), and gratitude, in turn, negatively predicted depression ( β = −0.20, t = −4.42, p < 0.001). The direct effect of self-compassion on depression remained significant after controlling for gratitude ( β = −0.43, t = −9.52, p < 0.001), indicating a complementary partial mediation. Bootstrap analysis with 5000 resamples further confirmed the robustness of the indirect effect. Conclusions The pivotal roles of self-compassion and gratitude in mitigating depression among young adults were explored, informing tailored intervention strategies for mental health practitioners.