<p>Heavy metals are highly nephrotoxic and may increase the risk of chronic kidney disease. However, the potential roles of inflammatory responses and dietary patterns in the relationship between heavy metals and kidney disease remain underexplored. This study examines the heavy metal exposure-inflammatory response-kidney function decline pathway and the modulating role of dietary patterns in heavy metal-induced kidney damage. Results from generalized linear models, restricted cubic spline models, and weighted quantile regression models show that exposure to individual heavy metals in blood and urine (except urinary mercury) is associated with a decrease in estimated glomerular filtration rate (eGFR) and an increase in urine albumin/creatinine ratio (UACR) and Systemic Inflammatory Response Index (SIRI) (except for blood mercury, urinary lead, and urinary mercury). Among blood heavy metals, lead (0.502) and cadmium (0.640) have the greatest impact on eGFR and UACR, respectively. Among urinary heavy metals, cadmium (0.463) and lead (0.902) have the greatest impact on eGFR and UACR, respectively. Moreover, exposure to multiple heavy metals in blood is linked to lower eGFR and higher UACR and SIRI, while exposure to multiple heavy metals in urine is associated with decreased eGFR, UACR, and SIRI. SIRI and Dietary Inflammatory Index (DII) are significantly associated with decreased eGFR and increased UACR, whereas Healthy Eating Index 2020 (HEI2020) is significantly associated with increased eGFR and decreased UACR. Mediation analysis indicates that individual or combined exposure to blood or urinary heavy metals affects kidney function via SIRI, with stronger mediation effects for individual heavy metal exposure than for combined exposure. Moderation analysis shows that DII exacerbates the nephrotoxicity of blood or urinary heavy metals, while HEI2020 has an ameliorating effect.</p>