Chronic stress is a global issue with detrimental effects on health and productivity, often leading individuals to adopt health-related coping strategies. This study uses an adapted Job Demands–Resources model to examine how various job demands and resources impact perceived stress and, consequently, the use of legal, prescription, and illegal drugs for enhancement purposes. Utilizing multiple waves from a nationwide sample of the working population in Germany (N = 7,705), structural equation models reveal that certain job demands increase perceived stress, while several resources mitigate it. Stress mediates the relationship between these factors and the use of legal and prescription drugs for cognitive enhancement. Illegal drug use was only directly impacted by selected job demands and resources. Thereby, this study expands the Job Demands–Resources model’s applicability to include health-related behaviors like drug use. Practically, it calls for multidimensional strategies to prevent potentially health-endangering drug use, including structural improvements and individual interventions.