Depression is a psychological condition characterised by alterations in the mood and behaviour regulation in women experiencing 50% greater burden of depression than men(1). Additionally, cardiovascular disease (CVD) is the leading cause of death in women globally while both CVD and depression can predict the incidence of each other reciprocally. Postmenopausal women particularly, during the menopause transition, are at increased risk of developing CVD and depression(2). Life’s Essential 8 (LE8), is a recently developed cardiovascular health assessment index comprising eight health behaviours and factors: dietary quality, physical activity level, nicotine exposure, sleep health, body mass index, blood glucose, non-high-density lipoprotein cholesterol, and blood pressure(3). It may be used to predict the risk of depression prevalence. This study investigated the association between LE8 and depression prevalence among postmenopausal women using the National Health and Nutrition Examination Survey (NHANES) 2011-2020 data. The LE8 score was calculated as the average of all eight components categorised into low (0–49), moderate (50–79), or high (80–100) cardiovascular health status(3). Depression severity was assessed using the Patient Health Questionnaire-9 (PHQ-9)(4). Complex survey-adjusted regression models were used. A total of 5472 postmenopausal women were included (mean age: 63.0 years), of whom 654 (12%) met the criteria for depression. The LE8 scores (mean ± SD) for those with and without depression were 53.2 ± 14.6 and 64.9 ± 14.7 (p < 0.001), respectively. Higher LE8 scores were significantly associated with lower odds of having depression (odds ratio [OR] per 10-point increase: 0.65, 95% CI: 0.60–0.72 , p < 0.001). Moderate and high cardiovascular health statuses were associated with a 54% and 88% lower odds of depression, respectively, compared to the low cardiovascular health status (p < 0.001). Furthermore, both health behaviour and health factor scores were inversely associated with depression (OR: 0.77, 95% CI: 0.73–0.82, and OR: 0.83, 95% CI: 0.77–0.90, respectively). A graded relationship was also observed across health behaviour and health factor statuses: moderate and high (vs. low) statuses were associated with 54–39% and 73–61% lower odds of depression, respectively (p < 0.001). Dietary quality was inversely associated with the likelihood of having depression (p = 0.02). Women in the 50th–74th percentile of the Healthy Eating Index (HEI-2015) score had 49% lower odds of depression (OR: 0.51, 95% CI: 0.29–0.91) and those in the ≥95th percentile had 77% lower odds of depression (OR: 0.23, 95% CI: 0.08–0.67) compared with lowest dietary quality group (1st–24th percentile). These findings suggest that the inverse association between total LE8 scores and depression supports the potential utility of integrating LE8 metrics into CVD management strategies to predict and mitigate depression in postmenopausal women.