Introduction Post-market monitoring has revealed an association between the use of leukotriene-modifying agents (LTRAs) and an increased occurrence of neuropsychiatric events. However, the results of observational studies have been inconclusive. Objective To assess the potential correlation between LTRAs exposure and depression in US outpatient adults. Method This population-based cross-sectional study used data from U.S. adults aged 20 to 59 years from the National Health and Nutrition Examination Survey (NHANES) 2007-2016 cycle. The Patient Health Questionnaire-9 was used to assess depression. Multivariable regression was used to evaluate the association between LTRAs exposure and depression. Results Among the 9,539 participants (mean age 40.4 years; 56.2% male), 602 (6.3%) were classified as having depression. LTRAs exposure was associated with a higher prevalence of depression (16.7% [50] vs. 6.0% [552]). In the multivariable logistic regression model LTRAs exposure was associated with depression (odds ratio [OR], 1.85; 95% confidence interval [CI], 1.22~2.83). An association between LTRAs exposure and depression was found in sensitivity analyses that conducted multivariable linear regression with the PHQ-9 score as a continuous variable (β, 0.86; 95% CI, 0.39~1.33), regardless of the PHQ-9 cut-off of 5 or 10, and the multivariable logistic regression results showed that LTRAs use increased the risk of depression (OR = 1.51 [95% CI, 1.12~2.05]; OR = 1.85 [95% CI, 1.22~2.83]). Conclusion Long-term LTRAs exposure is positively associated with depression in the adult outpatient population in the US. Therefore, the risk for depression in patients receiving long-term LTRAs treatment should be considered.