Objective <p>This study aimed to investigate the association between cancer history and depression risk, and to evaluate the potential mediating role of biological aging.&#xa0;</p> Methods <p>Data were collected from the 2005–2010 National Health and Nutrition Examination Survey (NHANES). Cancer status was assessed via questionnaire, while depression was evaluated using the Patient Health Questionnaire-9 (PHQ-9). Biological aging was defined by calculating phenotypic age acceleration (PhenoAgeAccel). Logistic regression methods were applied to explore associations between cancer, depression, and biological aging. In addition, subgroup analysis was conducted on the association between cancer and depression. Mediation analysis was employed to explore possible mechanisms underlying these relationships.</p> Results <p>This study included 12,999 participants aged ≥ 20 years, of which 1317 (10.13%) participants reported a history of cancer. After adjusting for confounders, logistic regression analyses revealed a significant association between cancer history and increased risk of depression (OR = 1.76, 95% CI 1.30–2.38). Subgroup analysis further demonstrated that this association was stronger among aged &lt; 60 years and inactivity participants (<i>p</i> for interaction &lt; 0.05). Additionally, higher level of PhenoAgeAccel was positively associated with depression risk, with participants in the highest quartile (Q4) having 84% higher odds of depression compared to those in the lowest quartile (Q1) (OR = 1.84, 95% CI 1.47–2.32). Mediation analysis demonstrated that 6.67% of the association between cancer and depression was mediated through PhenoAgeAccel.</p> Conclusions <p>Cancer experience may increase depression risk, with part of this association being mediated by PhenoAgeAccel.</p> Implications for Cancer Survivors <p>Cancer survivors require mental health interventions, and strategies to delay biological aging may help alleviate their depressive symptoms.</p>