Background <p>Frailty is an increasing public health concern, and diet is a key modifiable factor in its management. However, it remains unclear whether the dietary index for gut microbiota (DI-GM), which reflects gut-supporting dietary patterns, is associated with frailty. We therefore examined this association in U.S. adults. </p> Methods <p>In this population-based cross-sectional study, we used data from the National Health and Nutrition Examination Survey 1999–2018, including adults aged ≥ 40 years. Frailty was measured using a 49-item frailty index. We conducted weighted multivariable logistic regression to estimate the association between DI-GM and frailty. Restricted cubic spline (RCS) models were fitted to explore potential non-linear relationships. Threshold effect analyses were performed to identify cut-off points in this association.</p> Results <p>A total of 16,646 participants were included, of whom 5,862 were classified as frail. After multivariable adjustment, each point increase in DI-GM was associated with an 8% lower odds of frailty (OR = 0.92, 95% CI = 0.89–0.96). RCS analysis showed a nonlinear association between DI-GM and frailty (p for nonlinearity = 0.003), with an inflection point at a DI-GM score of 5. Segmental logistic regression indicated that when DI-GM ≥ 5, frailty risk decreased as DI-GM increased (OR = 0.84, 95% CI = 0.79–0.90). Further sex-stratified analysis revealed that higher DI-GM scores were linked to lower frailty risk in females (OR = 0.89, 95% CI = 0.86–0.93), while no such association was observed in males (OR = 0.97, 95% CI = 0.91–1.03; p for interaction = 0.005).</p> Conclusion <p>DI-GM was nonlinearly associated with frailty in middle-aged and older adults, with a negative association observed after reaching a specific threshold. Additionally, this association was observed in females but not in males. This is the first study to demonstrate a nonlinear, sex-specific relationship between DI-GM and frailty.</p>