This study aimed to comprehensively screen and assess the associations between potential environmental toxicants and depressive symptoms, and to evaluate whether systemic inflammation serves as a mediator. The study included 3427 participants from the National Health and Nutrition Examination Survey (NHANES) who had information on blood or urine concentrations of environmental toxicants and depression scores assessed by the 9-item Patient Health Questionnaire (PHQ-9). Sixty-two toxicants in 10 categories were analyzed, including acrylamide, arsenic, ethylene oxide, formaldehyde, iodine, metals, nicotine metabolites, polycyclic aromatic hydrocarbons (PAHs), volatile organic compound (VOC) metabolites, perchlorate, nitrate, and thiocyanate. The exposome-wide association study (ExWAS) and the deletion-substitution-addition (DSA) algorithm were used to assess associations with depression scores (PHQ-9 ≥5), adjusted for other important covariates. A mediation analysis framework was used to evaluate the mediating role of systemic inflammation assessed by peripheral white blood cell count. The study found that 27 chemical compounds or metals in 6 of the 10 categories of environmental toxicants were associated with the prevalence of depressive symptoms. Men and individuals younger than 65 years appeared more vulnerable to environmental toxicants than women and older individuals. Peripheral white blood cell count mediated 5% to 19% of the associations. The findings suggest that many common environmental toxicants are associated with depressive symptoms, providing potential targets for intervention measures and mechanistic research.This study aimed to comprehensively screen and assess the associations between potential environmental toxicants and depressive symptoms, and to evaluate whether systemic inflammation serves as a mediator. The study included 3427 participants from the National Health and Nutrition Examination Survey (NHANES) who had information on blood or urine concentrations of environmental toxicants and depression scores assessed by the 9-item Patient Health Questionnaire (PHQ-9). Sixty-two toxicants in 10 categories were analyzed, including acrylamide, arsenic, ethylene oxide, formaldehyde, iodine, metals, nicotine metabolites, polycyclic aromatic hydrocarbons (PAHs), volatile organic compound (VOC) metabolites, perchlorate, nitrate, and thiocyanate. The exposome-wide association study (ExWAS) and the deletion-substitution-addition (DSA) algorithm were used to assess associations with depression scores (PHQ-9 ≥5), adjusted for other important covariates. A mediation analysis framework was used to evaluate the mediating role of systemic inflammation assessed by peripheral white blood cell count. The study found that 27 chemical compounds or metals in 6 of the 10 categories of environmental toxicants were associated with the prevalence of depressive symptoms. Men and individuals younger than 65 years appeared more vulnerable to environmental toxicants than women and older individuals. Peripheral white blood cell count mediated 5% to 19% of the associations. The findings suggest that many common environmental toxicants are associated with depressive symptoms, providing potential targets for intervention measures and mechanistic research.