Background <p>Self-medication among healthcare workers poses serious risks to both personal health and patient safety. Operating room (OR) personnel, exposed to high-acuity care, irregular shifts, and systemic pressures, may be particularly vulnerable, yet comprehensive studies in this population remain limited.</p> Methods <p>This explanatory sequential mixed-methods study investigated self-medication among OR personnel during the COVID-19 pandemic. In the quantitative phase, 400 participants completed a validated 15-item questionnaire on self-medication behaviors, individual factors, and organizational/environmental determinants. In the qualitative phase, 20 semi-structured interviews were thematically analyzed. Integration was achieved through narrative weaving and a joint display.</p> Results <p>Self-medication prevalence was 65%. Quantitative analysis identified psychological stress (β = 0.35, <i>p</i> &lt; 0.001) and workplace pressures (β = 0.30, <i>p</i> &lt; 0.001) as the strongest predictors, with poor healthcare access and prior experience also contributing. Surgical technologists reported higher rates than nursing aides (<i>p</i> &lt; 0.05). Qualitative analysis revealed four themes: psychological strain, self-medication as coping, workplace pressures, and emotional consequences. Integration showed a reinforcing cycle in which stress and systemic barriers promoted self-medication, which in turn generated further emotional burden.</p> Conclusions <p>Self-medication among OR personnel during crises is prevalent and shaped by intertwined psychological and systemic factors. Interventions should address immediate stressors at the hospital level while implementing health-system policies that reduce structural barriers, to safeguard both healthcare providers and patient safety.</p> Clinical trial number <p>Not applicable.</p>