Organophosphorus pesticides (OPPs) are widely used pesticides, and previous studies showed that OPPs can increase the risk of central nervous system disorders (e.g., Parkinson's and Alzheimer's disease). However, few studies have comprehensively explored their association with depression in general adults. We analyzed data from 5206 participants aged 20 years or more based on four National Health and Nutrition Examination Survey (NHANES) cycles. OPPs exposure was estimated using measures of urinary concentrations for six OPPs metabolites. Survey-weighted generalized linear regression model (SWGLM) was used to explore the association of OPPs metabolites with depression. Subgroup analyses were performed by age (≦60 years and >60 years) and gender. The weighted quantile sum (WQS) regression model was used to explore the overall association of six OPPs metabolites with depression. In addition, The Bayesian kernel machine regression (BKMR) model was applied to investigate the interaction and joint effects of multiple OPPs metabolites with depression. The SWGLM showed that dimethyl phosphate (DMP) and dimethyl thiophosphate (DMTP), whether taken as continuous or quartile variables, had a positive correlation with depression. Diethyl phosphate (DEP) and dimethyl dithiophosphate (DMDTP) in the highest quartile were positively associated with depression compared to the lowest quartile. In subgroup analysis, we found that the effects of the above chemicals on depression existed in the male and young middle-aged population, while DMP was present in the female. There was a significant combined overall effect of six OPPs metabolites with depression [OR = 1.232, 95%CI: (1.011, 1.504)] in WQS. Furthermore, the BKMR model also showed a positive trend in the overall effect of six OPPs metabolites with depression. In conclusion, our results suggest that exposure to OPPs may increase the risk of depression in US adults. Men and young and middle-aged populations are more vulnerable to OPPs and the mixture of OPPs metabolites may induce depression.