Breast cancer (BC) and depression are globally prevalent problems. Numerous reviews have indicated the high prevalence of depression among BC survivors. However, the long-term impact of depression on survival among BC survivors has not been well explored. For this investigation, we aimed to explore the relationship between BC, depression, and mortality from a national random sample of adult American women. Data from the U.S. National Health and Nutrition Examination Survey (years 2005-2010) were linked with mortality data from the National Death Index up to December 31st, 2019. A total of 4719 adult women (ages 45 years and older) were included in the study sample with 5.1% having breast cancer and more than a tenth (12.7%) having depression. The adjusted hazard ratio (HR) for all-cause mortality risk among those with BC was 1.50 (95% CI = 1.05-2.13) compared to those without BC. In the adjusted analysis, the risk of all-cause mortality was highest among women with both depression and BC (HR = 3.04; 95% CI = 1.15-8.05) compared to those without BC or depression. The relationship between BC and mortality was moderated by cardiovascular diseases, anemia, smoking, age, PIR, and marital status. Our analysis provides vital information on factors that could be helpful for interventions to reduce mortality risk among those with BC and depression. In addition, given the higher risk of mortality with co-occurring BC and depression, collaborative healthcare practices should help with widespread screening for and treatment of depression among BC survivors.