Stigma has been associated with health-related outcomes such as medication adherence and quality of life (QOL) in patients with tuberculosis (TB); however, the mechanisms via which TB-related stigma interferes with specific outcomes are unclear. This study aimed to determine whether depressive symptoms were one of the mechanisms that mediated the associations between TB-related stigma and both medication adherence and QOL in patients with TB. A cross-sectional survey was conducted between October 1, 2013, and March 31, 2014, in Hubei Province, central China, and data were collected from 1,342 patients with TB, using a structured questionnaire that measured TB-related stigma, depressive symptoms, medication adherence, and QOL. Multiple imputation was used to account for missing data. Structural equation modeling was performed to assess the mediating effect of depressive symptoms on the associations of TB-related stigma with medication adherence and QOL. Mediation analyses showed that depressive symptoms partially mediated the association between TB-related stigma and medication adherence (standardized indirect effect = -0.16, 95% bias-corrected confidence interval [CI] [-0.19, -0.13], P < 0.01). Moreover, depressive symptoms fully mediated the association between TB-related stigma and QOL (standardized indirect effect = -0.17, 95% bias-corrected CI [-0.21, -0.14], P < 0.01). The results suggest that depressive symptoms played a key role in the relationships among TB-related stigma, medication adherence, and QOL in patients with TB. Therefore, the alleviation of depressive symptoms could be an important strategy for improving medication adherence and QOL in patients with TB.