Background <p>Ocrelizumab, a CD20-targeting monoclonal antibody, is a novel disease-modifying therapy for relapsing-remitting multiple sclerosis (MS) and primary progressive multiple sclerosis. Despite established efficacy in reducing relapse rates and disease progression, its impact on patient-reported outcomes (PROs) such as health-related quality of life (HRQOL), depression, and fatigue remains understudied.</p> Methods <p>This single-arm observational study included 30 MS patients receiving ocrelizumab at a tertiary center in Tehran, Iran. Selected PROs were assessed at 0-, 6-, and 12-month time points using the Medical Outcomes Study Short Form-36 for HRQOL, the Beck Depression Inventory-II for depression severity, and the Fatigue Severity Scale for fatigue. Longitudinal changes were analyzed using linear mixed models. Linear regression models were used to explore associations between patient demographics, clinical characteristics, and PRO scores at baseline.</p> Results <p>At baseline, participants had impaired HRQOL across multiple domains. Over 12 months, significant improvements were observed in general health (<i>P</i> &lt; .001), vitality (<i>P</i> = .032), and role-emotional (<i>P</i> = .012), along with increases in the mental (<i>P</i> = .026) and physical (<i>P</i> = .020) component summary scores. Depression severity decreased significantly (<i>P</i> = .029), but no significant changes were detected in fatigue levels (<i>P</i> = .818). Higher baseline EDSS was associated with lower physical functioning (<i>P</i> &lt; .001) and general health (<i>P</i> = .023).</p> Conclusion <p>Ocrelizumab treatment was associated with improved physical and mental HRQOL and reduced depression severity in MS patients.</p>