Background Sedentary behavior and depressive symptoms are commonly observed in cancer survivors. However, the combined impact of these factors on the mortality outcomes of cancer survivors remains unknown. Methods Cancer survivors from the National Health and Nutrition Examination Survey (NHANES) (2007-2018) were selected. Multivariate-adjusted Cox regression analyses were employed to examine the intendent and joint prognostic effects of sedentary behavior and depressive symptoms on the mortality outcomes of cancer survivors. Results A total of 2,460 US adult cancer survivors (men = 1,143 and women = 1,317) were included. Severe sedentary behavior (>= 8 h/day) was linked to higher all-cause [hazard ratio (HR) = 1.68, 95% confidence interval (CI): 1.36-2.09, p < 0.001] and noncancer mortality (HR = 1.80, 95% CI: 1.35-2.40, p < 0.001) in cancer survivors. Each additional hour of sedentary time increased the risk of all-cause (HR = 1.05, 95% CI: 1.02-1.08, p < 0.001) and noncancer mortality (HR = 1.07, 95% CI: 1.04-1.11, p < 0.001). Depressive symptoms (PHQ-9 >= 5) were also associated with higher all-cause (HR = 1.22, 95% CI: 1.01-1.48, p = 0.040) and noncancer mortality (HR = 1.27, 95% CI: 1.01-1.61, p = 0.045). In the joint analysis, cancer survivors with both depressive symptoms and severe sedentary behavior had the highest risk of all-cause mortality (HR = 2.06, 95% CI: 1.47-2.88, p < 0.001). Survivors with no depressive symptoms but severe sedentary behavior also had a higher risk (HR = 1.44, 95% CI: 1.10-1.88, p = 0.008). Additionally, the combination of depressive symptoms and severe sedentary behavior increased risks of cancer-specific (HR = 1.56, 95% CI: 1.04-2.34, p = 0.001), noncancer (HR = 1.86, 95% CI: 1.34-2.57, p < 0.001), and CMD-related mortality (HR = 1.74, 95% CI: 1.04-2.93, p = 0.037). In subgroup analysis, cancer survivors with endocrine-related and gastrointestinal cancers were more sensitive to these effects. Conclusion Our study highlighted the importance of considering both sedentary behavior and mental health in making effective long-term follow-up recommendations for cancer survivors.