Management of cardiovascular disease in pregnancy is important, yet the association between cardiovascular health and infertility is rarely reported. In this study, we aimed to explore the association between Life's Essential 8 (LE8), a novel cardiovascular health (CVH) measure, and infertility, and to investigate potential mediating mechanisms. This study investigated cross-sectional data from the 2013-2018 National Health and Nutrition Examination Survey. LE8 score (ranging from 0 to 100) was calculated as the unweighted average of eight CVH metrics. The association between LE8 and infertility was explored through weighted multiple logistic regression. Restricted cubic splines were used to explore nonlinear correlation. In addition, mediation analysis was conducted to investigate the role of oxidative stress and inflammatory markers systematically. After strict exclusion criteria, 1703 American women aged 18-45 years were included. After full adjustment, the LE8 score showed a negative correlation with infertility [per 1 SD increase, OR = 0.675, 95% CI: 0.553-0.824], with a linear dose-response relationship (non-linear P = 0.122). Similar linear negative correlations were found between health factor scores and infertility, with higher body mass index and glucose scores having a significantly lower risk of infertility. Stratified analyses showed a stronger inversed relationship between LE8 and infertility in younger populations. Moreover, mediation analysis revealed that uric acid concentration and lymphocyte count mediated the effect of LE8 on infertility (P <
0.05). LE8 and its subscale scores were linearly and negatively associated with infertility, which may be mediated in part through uric acid and lymphocyte count. Focusing on weight management and glycemic control can effectively reduce the risk of infertility.