Purpose This study examines associations between racial discrimination, mood disorders, and cardiovascular disease (CVD) among Black Americans. Methods Weighted logistic regression analyses on a nationally representative sample of Black Americans (n = 5022) in the National Survey of American Life (NSAL; 2001–2003). Racial discrimination and CVD were assessed via self-report. Mood disorder was measured using the World Health Organization Composite International Diagnostic Interview. Results Model-adjusted risk ratios (RR) revealed that participants with a history of mood disorder had greater CVD risk (RR = 1.28 95% confidence interval [CI] = 1.12, 1.45). This relationship was found specifically among those younger than 50 years of age (RR = 1.56, 95% CI = 1.27, 1.91). There was a significant interaction between racial discrimination and mood disorder in predicting CVD in the total (F = 2.86, 3 df, p = 0.047) and younger sample (F = 2.98, 3 df, p = 0.047). Participants with a history of mood disorder who reported high levels of racial discrimination had the greatest CVD risk. Conclusions The association between racial discrimination and CVD is moderated by history of mood disorder. Future studies may examine pathways through which racial discrimination and mood disorders impact CVD risk among Black Americans.