Objectives <p>This retrospective study investigates the impact of multimorbidity, polypharmacy, and drug interactions on postoperative outcomes and patient management in individuals diagnosed with oral squamous cell carcinoma (OSCC). The study aims to identify treatment-related risks within surgical care pathways and explore the role of pharmacological complexity in patient prognosis.</p> Materials and methods <p>Clinical data from OSCC patients undergoing surgical treatment were retrospectively analyzed. Key parameters included the presence of multiple chronic conditions (multimorbidity), the number and types of prescribed medications (polypharmacy), and the use of potentially inappropriate medications (PIMs) according to the PRISCUS list. Primary outcomes included postoperative complications, wound healing, readmission, reoperation rates, and mortality.</p> Results <p>Multimorbidity and polypharmacy were significantly associated with increased rates of postoperative complications, delayed wound healing, and higher rates of hospital readmission. PIMs were prescribed in 13.7% of patients and were linked to elevated mortality. Importantly, patients who did not receive PRISCUS-listed medications had a 55% lower risk of readmission and a 52.3% lower risk of reoperation, suggesting a potential benefit of medication optimization in perioperative care.</p> Conclusions <p>The findings emphasize the relevance of multimorbidity and complex medication regimens in influencing surgical outcomes in OSCC. Systematic preoperative risk assessment and medication review are critical to reducing complications and improving recovery.</p>