ObjectiveThis cross-sectional study examined the influence of sedentary behavior (SB) time substitution with physical activity (PA) on depressive symptoms among adults with overweight/obesity. SB time was replaced with equal amount of walking/bicycling or leisure-time moderate-to-vigorous PA (MVPA). MethodsData of the 18344 adults, who were overweight and obesity was obtained from the National Health and Nutrition Examination Survey 2006–2018. PA of participants was measured by the Global Physical Activity Questionnaire. Depressive symptoms, including overall, somatic, and cognitive depressive symptoms were assessed by the Patient Health Questionnaire-9 (PHQ-9). Isotemporal substitution model based on weighted multiple linear regression was used to assess the association of SB time substitution with PA on depressive symptoms. ResultsIndependent model analysis showed that 30 min/day SB time was significantly associated with higher PHQ-9 depressive symptoms, while engage in walking/bicycling or leisure-time MVPA for 30 min/day was associated with lower depressive symptoms. Isotemporal substitution analyses revealed that replacing 30 min/day SB time with equal amount of walking/bicycling or leisure-time MVPA was associated with significant lower PHQ-9 total scores (walking/bicycling: β = −0.088, 95%CI = −0.129, −0.047, P < 0.01; MVPA: β = −0.160, 95%CI = −0.185, −0.134, P < 0.01). Moreover, cognitive depressive symptoms (walking/bicycling: β = −0.035, 95%CI = −0.058, −0.013, P < 0.01; MVPA: β = −0.074, 95%CI = −0.088, −0.060, P < 0.01), and somatic depressive symptoms (walking/bicycling: β = −0.053, 95%CI = −0.075, −0.030, P < 0.01; MVPA: β = −0.085, 95%CI = −0.100, −0.071, P < 0.01) were also significantly lower after replacing SB time with either walking/bicycling or MVPA. However, replacing 30 min/day PA with SB time represented with higher depressive symptoms. ConclusionsReplacing SB time with walking/bicycling or MVPA is beneficial in lowering the depressive symptoms among overweight/obese adults. Owing to the benefits of PA on depression, strategies promoting PA participation, are necessary for better social/mental well-being and healthy society.