Depression is a common mental health issue that can lead to various physical and psychological diseases. However, the relationship between depressive symptoms and premature death remains unclear.In this study, we used data from the National Health and Nutrition Examination Survey (NHANES) 2011-2014 to assess the relationship between depressive symptoms and premature mortality and the potential influence of mitochondrial function on this relationship. The Patient Health Questionnaire-9 (PHQ-9) was used to assess the severity of depressive symptoms. Mortality data were obtained from the National Death Index (NDI). Mitochondrial function was assessed by measuring methylmalonic acid (MMA) levels. Multivariate logistic regression was used to assess the association between depressive symptoms and premature mortality, controlling for demographic, lifestyle, and disease-related factors. Restricted cubic splines were plotted, and propensity score matching (PSM) was used to create balanced groups. Finally, mediation analysis was performed to investigate the mediating role of MMA in the association between depressive symptoms and premature mortality.This study included a total of 6599 participants. The results showed a substantial positive association (odds ratio [OR] = 1.452; 95 % confidence interval [CI], 1.038-2.031; p < 0.05) between depressive symptoms and premature mortality. The significance of this relationship was maintained after PSM analysis (OR = 2.370; 95 % CI, 1.749-3.212; p < 0.01). Mediation analysis showed that MMA partially mediated this relationship, with a mediation proportion of 4.1 %.This study indicates that depressive symptoms significantly increases the risk of premature death and mitochondrial dysfunction partially mediates this positive relationship. Additional prospective and experimental studies are warranted to verify these findings.Copyright © 2025. Published by Elsevier B.V.