Multiple sclerosis (MS) is the most prevalent immune-mediated disease affecting the central nervous system. A treatment strategy with multiple therapies is a frequent clinical scenario. Unmonitored multi-drug use can lead to adverse outcomes, higher health care costs and medication non-adherence. The primary aim of this study was to evaluate the frequency of polypharmacy and related clinicodemographic factors in a single-center MS patient cohort. Furthermore, medication aspects of therapy management were examined. After the patients agreed to participate in the study, data were collected through patient interviews, patient records and clinical investigations. Subsequently, a statistical data analysis regarding various medication subgroups and polypharmacy (use of at least five drugs) was performed. Polypharmacy was observed in 56.5% of the patients (N = 306). High degrees of disability (odds ratio [OR] = 1.385), comorbidities (OR = 4.879) and inpatient treatment (OR = 5.146) were associated with a significantly higher risk of polypharmacy (p ≤ 0.001). Among patients with polypharmacy, disease-modifying drugs, antihypertensives, gastrointestinal drugs, thrombosis prophylactics, osteoporosis medications and sedatives were frequently used. In summary, polypharmacy plays a large role in MS patients, especially in those with higher degrees of disability, those with comorbidities and those treated in an inpatient setting.