Objectives: The purpose of this study was to explore the relationship between skeletal muscle disorders (SMD), occupational stress (OS) and depressive symptoms (DS) among firefighters. Material and Methods: A cross-sectional survey was conducted among firefighters in Chongqing, China. Descriptive statistic and correlation analyses were performed by using SPSS 26.0. AMOS 24.0 was used to construct the structural equation modeling between SMD and DS. The mediating effect of OS was also evaluated. Results: The results demonstrate that SMD can predict DS (β = 0.25, p < 0.001) and OS (β = 0.39, p < 0.001) positively, OS positively predicted DS (β = 0.39, p < 0.001) after controlling for SMD. Additionally, OS has a partial indirect effect between DS and SMD (indirect effects = 0.209, 95% CI: 0.093–0.372, p < 0.001). Conclusions: Occupational stress has a partial indirect effect between SMD and DS among firefighters. Skeletal muscle disorders could affect DS not only directly, but also indirectly, by affecting OS. These findings may be of great significance and contribution to the future research of firefighters’ occupational health. Int J Occup Med Environ Health. 2025;38(1)