<p>Kidney stones are a prevalent urological disorder and a growing public health concern due to their high burden and recurrence rates. Organophosphate esters (OPEs), widely used as flame retardants and plasticizers, are ubiquitous environmental contaminants that have been linked to various adverse health outcomes. This study aimed to investigate the association between urinary concentrations of OPE metabolites and the prevalence of kidney stones among U.S. adults, using data from four 2011–2018 cycles of the National Health and Nutrition Examination Survey. In this cross-sectional study, our analysis revealed that elevated urinary levels of bis(1,3-dichloro-2-propyl) phosphate (BDCPP) and diphenyl phosphate were significantly associated with a higher prevalence of a self-reported history of kidney stone. To evaluate both individual and joint effects of OPEs exposure, we employed multivariable logistic regression, quantile g-computation, and Bayesian kernel machine regression. These approaches consistently demonstrated a positive association between cumulative OPEs exposure and kidney stone prevalence, with BDCPP identified as a predominant positive contributor. Exploratory mediation analysis suggested that alkaline phosphatase and electrolyte indicators (phosphorus and chloride) might partially explain the observed associations. Additionally, network toxicology and molecular docking analyses identified three inflammation-related targets—ADORA2B, P2RX7, and SLC11A2—that might be involved in the effects of OPEs on kidney stone formation. These findings suggested that OPEs exposure was associated with kidney stone prevalence and highlighted the need for prospective and mechanistic studies to elucidate the underlying biological pathways.</p> Graphical abstract <p></p>