Introduction: Recent studies show a growing body of evidence suggesting that users of cannabis have consistently higher prevalence rates of depressive disorders in comparison to non-users. Besides, it can be used as a highly effective treatment for depression and other mood disorders. Methods: A study with a cross-sectional design was conducted with data from respondents aged 25-64 who participated in the 2018 Behavioral Risk Factor Surveillance System (BRFSS) survey. The population was assessed for the baseline characteristics, followed by a bivariate analysis, a multivariate logistic regression to control any confounders, and assess the association between the use of cannabis and depression. Results: The sample included 57,757 individuals. The unadjusted binary logistic regression indicated that those who use cannabis are 93% more likely (OR: 1.93) to have a diagnosis of depression. On the other hand, the adjusted analysis indicated that those who use cannabis are 78% more likely (OR: 1.78) to have a diagnosis of depression. Other variables including participants under the age of 45 years were significantly associated with the diagnosis of depression (OR: 1.35). Moreover, participants with an education without a high school diploma (OR: 0.54), and those having a full-time commitment (OR: 0.37) were significantly less likely to have a diagnosis of depression. Conclusion: Findings suggest that selected U.S. participants who use cannabis have an increased risk to report depression. Furthermore, factors such as age, level of education, and a persons time commitment status were found to have a significant influence on whether a diagnosis of depression is present.