Background Bisphenol F (BPF) and bisphenol S (BPS) are replacing bisphenol A (BPA) in the manufacturing of products containing polycarbonates and epoxy resins, however, the effects of these substitutes on the risk of cardiovascular disease (CVD) have not been assessed. Objective To examine the association of urinary BPS and BPF with the CVD risk in a U.S. representative population. Method A cross-sectional data with 1,266 participants aged 20 to 80 years from the 2013–2016 National Health and Nutrition Examination Survey (NHANES) was analyzed. The logistic regression was used to assess the association between BPF, BPS and CVD. The Bayesian kernel machine regression (BKMR) model was applied to assess the mixed effect. Results A total of 138 patients with CVD were identified. After adjusting for potential confounding factors, T3 concentration of BPS increased the risk of total CVD (OR: 1.98, 95%CI: 1.20–3.28). When stratified by age, we found that BPS increased the risk of CVD in the 50–80 age groups (OR:1.40, 95%CI: 1.05–1.87). BPS was positively associated with the risk of stroke and T3 of BPS increased the stroke risk by 3.46 times (95%CI: 1.09–10.95). No significant association was observed between BPF and CVD. Although BKMR model did not identify the mixed exposure effect of BPS, the risk of CVD increased, with the increase of compound concentration. Conclusion Our results suggest that BPS may increase the risk of total CVD and stroke in the U.S population, and prospective studies are needed to confirm the results.