Thyroid nodule (TN) has been becoming a great concern worldwide due to its high incidence. Although some studies have reported associations between trace elements exposure and the risk of TNs, the linkage was not inconclusive. The present study aimed to identify the association of selected serum trace elements (Ca, Mg, V, Fe, Co, Cu, Zn, Se, Mn and Mo) with TNs among general adults. A cross-sectional study was conducted in January 2021 in Chengdu, China. 1282 subjects completed the questionnaire and gave at least one human biological material after an overnight fast, venous blood, and urine, including 377 TN participants defined through ultrasound. Various trace elements in serum specimens were determined by inductively coupled plasma mass spectrometry. Thyroid functions were tested by chemiluminescent microparticle immunoassay (CMIA). The associations between trace elements levels and the risk of TNs were examined by restricted cubic splines (RCS) regression and bayesian kernel machine regression (BKMR) models. TNs were more common in females (P < 0.001) and in the elderly (P < 0.001) and that they were also frequently associated with fertility, marital status, annual household income, drinking, anxiety, vitamin supplement, tea consumption, hypertension and hyperlipidemia. After adjusting for confounders by a propensity score matching model, the association between trace elements concentrations and TNs risk was found to be statistically insignificant in the RCS (P for nonlinear > 0.05) and BKMR models. FT3 or T4 (total or free) increased significantly with increasing total trace elements mixture levels. In TI-RADS-4 TN subjects, TPO-Ab level increased significantly with increasing total trace elements mixture levels in the high-dose range. Ca, Zn, Mo at their 75th percentile showed positive individual effects on TPO-Ab, which was examined to be interactive. The detection of trace elements for TNs in general adults may be of no significance, but once individuals classified as TI-RADS-4 TNs are detected with abnormal TPO-Ab, Ca, Zn and Mo level are recommended to measure. The substantive association on it still needs to be continuously explored in the future.