Abstract Objective The Life's Simple 7 (LS7) metrics were developed by the American Heart Association to define ideal cardiovascular health. The impact of LS7 on frailty among older adults remains unclear. Our objective was to examine the association between the cardiovascular health score and risk of frailty among older adults. Designs, Settings, and Participants Data from the National Health and Nutrition Examination Surveys (NHANES) 1999-2018 was used. We included 9242 community-dwelling adults aged ≥ 65 years. The LS7 score was calculated for all participants. Frailty was measured with the 40-item frailty index, and a frailty index score of > 0.21 was defined as ‘frailty’. Log-binominal regression and negative binomial regression were conducted to estimate the association between LS7 and frailty. Mediation analysis was used to estimate the mediating effects of inflammatory indicators on the association. Results The weighted average of frailty index score was 0.18, and 3206 participants (34.8%) were identified as ‘frailty’. Participants with high LS7 scores had significantly lower frailty index score and prevalence of frailty than those with low LS7 scores. In fully adjusted log-binominal regression models, with total score < 6 as a reference, the ORs (95% CIs) for frailty were 0.79 (0.65, 0.96), 0.66 (0.54, 0.80), 0.50 (0.39, 0.65), and 0.39 (0.29, 0.52) for total score = 6, total score = 7, total score = 8, and total score > 8, respectively. When LS7 score analyzed as a continuous variable, per 1-point increase in the LS7 score was associated with a 16% decrease in the risk of frailty (P < 0.001). In negative binominal regression models, the adjusted PRs (95% CIs) for frailty were 0.96 (0.93, 1.00), 0.94 (0.91, 0.97), 0.91 (0.87, 0.95), and 0.85 (0.82, 0.88) for total score = 6, total score = 7, total score = 8, and total score > 8, respectively. For each 1-point increase in the LS7 score, the risk of frailty decreased by 3% (P < 0.001). No significant interactions were observed in subgroups stratified by age, sex, race, body mass index, smoking status, alcohol consumption, and self-reported health status. Causal mediation analysis indicated that inflammatory factors including blood cell count, neutrophil count, and C-reactive protein positively mediated the association of LS7 with frailty, with a mediating proportion of 0.0357 (P = 0.01), 0.0741 (P < 0.001), and 0.0524 (P = 0.012), respectively. Conclusions In a nationally representative sample of U.S. adults, increased exposure to EO was independently related to an increased prevalence of frailty.Association between LS7 and frailtySubgroup analysis