Purpose: Preventing the effects of physical vulnerability is a practical approach to improving older adults’ depressive symptoms. This study aims to examine the relationship between gender differences related to muscle strength and depressive symptoms mediated by perceived stress. Methods: In this cross-sectional study, data from 2,705 older adults (65 years old or older) from the Korea National Health and Nutrition Examination Survey VII 2016 and 2018 were analyzed. The moderated mediation model was developed; the outcome, independent, mediation, and moderated mediation variables in the literature-based research model were depressive symptoms, muscle strength, perceived stress, and gender, respectively. Results: Perceived stress had a mediating effect on the relationship between muscle strength and depressive symptoms. The indirect effect of muscle strength on depressive symptoms mediated by perceived stress was β = -.02 (95% CI:-0.03~-0.01). The moderated mediation model demonstrated that the interaction term of handgrip strength and gender negatively affected perceived stress, which indicated that gender moderated the mediating model of perceived stress on the association of muscle strength and depressive symptoms (β = -.01, p <.05). The conditional indirect effect model was insignificant in the male group (β = -.00, 95% CI:-0.01~0.01) but significant in the female group (β = -.01, 95% CI: -0.02~0.00). Conclusions: Perceived stress mediated the relationship between muscle strength and depressive symptoms. However, the effect differed by gender. A stress-mediated depressive symptoms intervention program for older adults should be developed to consider women’s needs.