The prevalence of depression continues to rise, and it has a high death and disability rate. Life's Essential 8 (LE8) is an updated measurement of cardiovascular health (CVH), and a higher score of LE8 represents healthier CVH. Our study aimed to investigate the association between the LE8 and depression among adults. This cross-sectional study used data from the National Health and Nutrition Examination Survey. CVH was measured by using LE8 according to American Heart Association definitions. Depression was assessed by the 9-item Patient Health Questionnaire (PHQ-9). Weighted univariable and multivariable logistic analyses were performed to investigate the association of LE8 with depression. Subgroup analyses were also conducted in different groups based on age, gender, race, body mass index (BMI), smoking, arthritis, cardiovascular disease, and chronic kidney disease. A total of 22,149 participants were included in the database, with a mean LE8 score of 71.27. The prevalence of depression was 7.32%. The mean scores of LE8 in health behaviors and health factors were 73.28 and 69.26, respectively. After adjustment of potential confounders, a higher LE8 score was associated with lower odds of depression (odds ratio = 0.27, 95% confidence interval: 0.20-0.37). A similar association was observed in the subgroup analyses. Higher overall LE8 scores and higher scores for each component (diet, physical activity, nicotine exposure, sleep duration, BMI, blood lipids, blood glucose, and blood pressure) were associated with lower odds of depression. LE8 score might be a useful tool for both cardiologists and psychiatrists in screening for and monitoring physical and mental health. Primary care physicians also could better tailor care and interventions to address both physical and mental health needs.