This cross-sectional study aimed to explore the combined effects of depression and obesity on ischemic heart disease and its subtypes. Data from the National Health and Nutrition Examination Survey 2007-2018 were used. A total of 29,050 participants aged 20 years or older were included in the analyses. Logistic regression models and restricted cubic spline models were applied to evaluate the associations between depression symptom and ischemic heart disease. There were significant correlations between depressive symptoms and ischemic heart disease [OR and 95% CI 2.44 (1.91, 3.10)] and its subtypes: coronary heart disease [2.32 (1.67, 3.23)], heart attack [2.18 (1.71, 2.78)], and angina [2.72 (1.96, 3.79)].The synergistic effects of depression with obesity (BMI ≥ 30) and central obesity (waist ≥ 102/88 cm for men/women) on ischemic heart disease were estimated and expressed using the relative excess risk due to interaction (RERI) and the attributable proportion due to interaction (AP). The RERI and AP with 95% CIs of depression and central obesity for ischemic heart disease were 1.10 (0.01, 2.19) and 0.35 (0.06, 0.64). When we analysed the other three subtypes of ischemic heart disease, we only found depressive symptoms and central obesity could have a meaningful synergistic effect on heart attack (RERI: 0.84 (- 0.28, 1.96) AP: (0.31 (0.00, 0.69)).