Exposome recognizes that humans are constantly exposed to multiple environmental factors, and elucidating the health effects of complex exposure mixtures places greater demands on analytical methods. We aimed to explore the association between mixed exposure to metals and hyperuricemia (HUA), and highlight the potential of explainable machine learning (EML) and causal mediation analysis (CMA) for application in the analysis of exposome data. Pre-pandemic data from the National Health and Nutrition Examination Survey (NHANES) 2011–2020 and a total of 13780 individuals were included. We first used traditional statistical models (multiple logistic regression (MLR) and restricted cubic spline regression (RCS)) and EML to explore associations between mixed metals exposures and HUA, followed by the CMA using the 4-way decomposition method to analyze the interaction and mediation effects among BMI or estimated glomerular filtration rate (eGFR), metals and HUA. The prevalence of HUA was 18.91% (2606/13780). The MLR showed that mercury (Q4 vs Q1: OR = 1.08, 95% CI:1.02–1.14) and lead (Q4 vs Q1: OR = 1.23, 95% CI:1.13–1.34) were generally positively associated with HUA. Higher concentrations of lead, mercury, selenium and manganese were associated with the increased odds of HUA, and BMI and eGFR were the top two variables attributable to the risk of developing HUA in the EML. Subgroup analyses from the MLR and EML consistently demonstrated the positive relationship between exposure to lead, mercury and selenium in participants with BMI <25 kg/m2 and BMI ≥30 kg/m2. BMI mediated 32.12% of the association between lead exposure and HUA, and the interaction between BMI and lead accounted for 3.88% of the association in the CMA. Heavy metals can increase the HUA risk and BMI or eGFR can mediate and interact with metals to cause HUA. Future studies based on exposome can attempt to utilize the EML and CMA. Display omitted •The widest possible range of data on metals and covariates form NHANES were involved that were openly available.•Two innovative methods (explainable machine learning and causal mediation analysis) were applied to exposome data.•Higher concentrations of lead, mercury, selenium and manganese were associated with the higher risk of hyperuricemia.•BMI and eGFR can mediate and interact with metals to cause hyperuricemia, especially for Pb and Hg.