Objectives: Multiple sclerosis (MS) is a disabling neurological disorder with significant adverse effects on patients' quality of life (QoL). Despite the increased prevalence of MS in Arabian Gulf countries in recent years, no study has assessed the impact of MS on the health-related QoL (HRQoL) of Omani patients. Therefore, the objective of this study was to determine the impact of MS on HRQoL of Omani patients using the validated disease-specific self-administered MS International QoL (MusiQoL) instrument. Methods: We conducted a descriptive cross-sectional survey between April and December 2019 on 177 Omani patients with MS attending Sultan Qaboos University Hospital and Khoula Hospital in Oman using the MusiQoL instrument. Results: The majority (51.4%) of patients had poor HRQoL, and 48.6% had moderate HRQoL. We found that being > 30 years, female, married, separated, widowed, or divorced, and having visual and sleep problems resulted in poorer HRQoL scores. Among the different HRQoL components, relationships with the healthcare system and relationships with family and friends were the most affected by the disease process. Our results also showed that psychological wellbeing and coping domains of MusiQoL questionnaires are significantly reduced in females compared to males. Conclusions: Understanding the HRQoL of Omanis with MS provides valuable knowledge that could help optimize the management of this disease.