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Background: Frailty is common and not limited to older age group. Serum α-Klotho works as a biomarker of anti-aging effect. However, there is limited research about the relationship between them in middle-aged and older people and controversy still exists. Methods: Based on data from National Health and Nutrition Examination Survey (NHANES) 2007–2016, we constructed weighted logistic regression models and conducted sensitivity tests to investigate the correlation between frailty and α-Klotho among people aged 40 to 79. And then their relationship was visualized by Restricted Cubic Spline (RCS). Finally, the stratified analyses and interaction tests of covariables was presented in the forest plot. Results: A total of 7052 individuals were involved in this study, with mean age of 62.76 ± 0.18 years and females accounting for 51.05%. 2554 of them were in “frailty”. After adjustment for relevant covariables, weighted logistic regression models showed that the odds ratio and 95% confidence interval [ORs (95%CI)] of correlation between frailty and Natural Logarithm(ln)-transformed α- Klotho[ln(α-Klotho)] was 0.63 (0.50, 0.79); we then performed a sensitivity analysis and found that the results remained stable. In model 3, individuals in quartiles 2, 3, and 4 showed statistical differences compared with the lowest ln(α-Klotho) quartiles, ORs (95% CI) were 0.74 (0.59, 0.93), 0.72 (0.57, 0.91), 0.71 (0.57, 0.87), respectively. Subsequently, non-linear associations were exhibited by RCS (p<0.001). The turning point for α-Klotho and ln(α-Klotho) were 785.7(pg/ml) and 6.67, respectively. Finally, analysis of the relationship between different levels of ln(α-Klotho) and frailty in different populations revealed differences between groups. The results of the interaction test showed that no other covariables had significant interaction with serum α-Klotho in our study. Conclusion: The L-shaped and negative correlation was found between α-Klotho and frailty among people aged 40 to 79 in the NHANES from 2007 to 2016.