AIM: Numerous studies have revealed the decisive role of serum chloride in the outcome of specific patients. However, the potential role of serum chloride in general populations has been rarely investigated. This study aims to assess the association of serum chloride with MetS risk in the general population. METHODS: A total of 13,290 adult participants were obtained from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2018. The association between serum chloride and MetS was investigated using weighted logistic regression analyses. The weighted restricted cubic spline (RCS) was constructed based on the fully adjusted model to explore its dose-response relationship. Further stratified analyses were also conducted. All data and analyses were conducted using the "Survey" package in R software (Version 4.4.1). RESULTS: The average age of this population was 48.20 ± 0.35, the average BMI was 29.42 ± 0.12 kg/m CONCLUSION: This study suggested a potential inverse relationship between serum chloride levels and MetS risk. Understanding this link may offer fresh perspectives on preventing and treating MetS, presenting new therapeutic targets and strategies for public health improvement.