Background: Many risk factors related to altered circadian rhythms impact the health of night-shift hospital workers (NSHW), resulting in mental and somatic disorders. Easy access to psychoactive substances (PS) may facilitate addictive behaviors in NSHW. They are also exposed to a stressful work environment, which may further affect sleep quality. This study aimed to explore the link between sleep deprivation, work-related psychosocial stress and psychoactive substance use as a self-medication response in NSHW. Methods: Qualitative study to verify the plausibility of the self-medication theory applied to addictive behaviors. Semi-structured interviews (N = 18 NSHW) and thematic analysis, following consolidated criteria for reporting qualitative research recommendations. Results: Stigma against NSHW was a primary element of a stressful work environment. The stressful and stigmatizing environment, together with night-shift work, further affected NSHW sleep and their mental and physical health. The use of PS appeared to be for self-medication, encouraged by social and professional environments, source(s) of stress, discrimination, and isolation. The work environment, through aggravated sleep disorders, led NSHW to use nonprescribed sleeping pills. Alcohol after work and smoking were used as a social break but also as a means to reduce stress. Conclusion: Anti-stigma interventions in the healthcare setting and screening of mental/somatic disorders in NSHW can help reduce harmful self-medication behaviors and improve hospital care in the COVID-19 era.