<p>The opioid epidemic has plagued the United States for over two decades and continues to be a pervasive issue for workers and employers. While the factors contributing to opioid use are multifaceted, we drew from the job demands-resources model and the self-medication hypothesis to examine how the opioid epidemic intertwines with two co-existing issues: economic stress and the mental health crisis. Using a three-wave study of employed adults (<i>N</i> = 318), we examined depressive symptoms as a mediator of the subjective economic stressors (i.e., job insecurity, perceived income inadequacy) and opioid use (i.e., prescription opioids, illicit opioids) relationship. The findings supported depressive symptoms as an explanatory mechanism for the relationships of job insecurity and perceived income inadequacy with prescription opioid use but not illicit opioids. We also tested the bidirectional effects of opioid use on job insecurity and perceived income inadequacy, as mediated by depressive symptoms; however, these effects were not significant. Taken as a whole, our findings offer evidence supporting a relationship between subjective economic stress, mental health, and opioid use, with the specific pattern of effects differing based on the type of opioid use.</p>