<p>Social frailty is a major risk factor for adverse health outcomes in older adults. This cohort study explored the mediating role of social frailty in the relationship between depressive symptom trajectories and all-cause mortality among middle-aged and older adults. A nationwide cohort of 6653 participants aged ≥ 45&#xa0;years was included in this study. Longitudinal courses of depressive symptoms measured using the Center of Epidemiologic Studies Depression Scale (10-item version) from 2006 to 2014 were classified using growth mixture modeling. The associations of depressive symptom trajectories with all-cause deaths until 2022 were determined using a Cox model. Mediation analyses were conducted to evaluate the mediating role of social frailty on these associations. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed. Four trajectories of depressive symptoms were identified: stable-low (<i>n</i> = 5462; 82.1%), decreasing (<i>n</i> = 334; 5.0%), increasing (<i>n</i> = 708; 10.6%), and stable-high (<i>n</i> = 149; 2.2%). Compared to those experiencing stable-low trajectory, individuals experiencing increasing (HR 1.42, 95% CI 1.21–1.66) and stable-high (HR 1.48, 95% CI 1.11–1.97) trajectories had an elevated risk for all-cause mortality. The mediation analyses showed that social frailty explained 46.3% and 40.9% of the associations between increasing and stable-high trajectories and all-cause mortality, respectively, compared to stable-low trajectory. This study found that social frailty may be a major psychosocial mechanism linking poor late-life depressive symptom trajectories to mortality risk. Policy implementation is warranted to reduce social frailty in older adults with depressive symptoms.</p>