Abstract Background Evidence regarding the benefits of dietary supplements against frailty is lacking. Therefore, we aimed to examine the association between the use of dietary supplements and frailty. The analyses were stratified by sex to consider the sexual dimorphism in frailty. Methods This study used national, cross-sectional survey data from South Korea, namely the Korea National Health and Nutrition Examination Survey (KNHANES, 2018-2020). Adults aged 50 years were included. Data for up to four supplements were collected for each participant. A 46-item frailty index was constructed to assess frailty. All percentages (%) were weighted to represent the national population. The association between the use of dietary supplements and frailty was investigated using a linear regression analysis with socioeconomic/lifestyle factors and the amount of nutrient intake from diet included as covariates. Results Of the included 27,384 older adults, 57.28% were women. The proportion of supplement users was significantly higher in women (64.31% vs. 77.71%, p < 0.001). Any supplement use was negatively associated with frailty (B = -0.015, p < 0.001), and the association was more significant in women (Any supplement use * women: B = -0.012, p = 0.002). From the multivariable regression analysis stratified by sex, the use of red ginseng (men: B = -0.019, women: B = -0.015) and calcium (B = -0.027, women: B = -0.012) were negatively associated with frailty in both sexes while the statistical significance for vitamin C was found only in men (B = -0.020) (all p < 0.05). Conclusions Our findings demonstrated a significant negative association between the use of dietary supplements and frailty. The associations varied by type of supplements and by sex. The findings should be validated using prospective data. Key messages • Red ginseng and calcium supplements were negatively associated with frailty in both sexes. • We assessed frailty using frailty index which highlights the potential role of dietary supplements beyond the context of physical or musculoskeletal function.