Exposure to metals can trigger a series of diseases by dysregulating the human immune system, but there is still a lack of systematic studies assessing the independent and combined effects of exposure to metals on immune function in the general population, particularly concerning inflammation markers. This cross-sectional study was designed to mainly examine the associations between urinary metal mixtures and inflammatory markers, including white blood cell (WBC), platelet count (PLT), mean platelet volume (MPV), MPV/PLT ratio (MPR), platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR). A total of 3451 participants aged ≥20 years were selected from the 2013-2016 National Health and Nutrition Examination Survey. Generalized linear models were used to investigate the relationships of exposure to single metals on inflammatory markers. Associations between coexposure to multiple metals and inflammatory markers were determined using weighted quantile sum regression and quantile g-computation. Barium, cadmium, lead, thallium, and cobalt showed significant associations with MPV, PLR, and NLR. Metal mixtures showed a negative association with MPV, while they had positive associations with PLR and NLR. Overall, our study highlights the significant effects of multiple metals exposure on inflammation markers, including MPV, PLR, and NLR, among U.S. adults. Thereinto, uranium, cadmium, and cobalt were identified as major contributors. Further prospective studies representative of other countries are warranted to either validate or refute our findings.