<p>Cardiovascular-kidney-metabolic (CKM) syndrome is a critical determinant of mortality. Research has demonstrated that environmental factors are significant risks for CKM, and heavy metal exposure contributes to various diseases. However, the impact of heavy metal on CKM syndrome has not been evaluated. This investigation was to elucidate the link between heavy metal and advanced CKM stages from National Health and Nutrition Examination Survey (NHANES). Multivariate logistic regression, weighted quantile sum (WQS) model, restricted cubic spline (RCS), and subgroup analysis were employed to analyze the relationships. Mediation analysis explored whether inflammation mediated the effects. 4,400 participants were included in this study, with 872 diagnosed with advanced CKM stages. The results revealed a positive and linear association of heavy metal, including cadmium (Cd), cobalt (Co) and lead (Pb), with advanced CKM stages. Furthermore, heavy metal mixtures were also found to correlate with advanced CKM stages, showing that Cd, Co and Pb contributed the weights of 32.40%, 34.20% and 22.80%, respectively. Additionally, systemic immune-inflammation index (SII) was identified as a mediator in the association of Cd and Co with advanced CKM stages, accounting for 2.69% and 3.91%, respectively. Our findings suggest that heavy metal exposure, especially Cd, Co, and Pb, might contribute to the development of CKM syndrome. More studies are needed to investigate the relationship between heavy metal and CKM syndrome.</p>