Background: Neuromyelitis Optica Spectrum Disorder (NMOSD) is a rare autoimmune demyelinating condition primarily characterized by recurrent attacks of optic neuritis and myelitis, leading to significant disability and reduced quality of life. Traditionally, plasma exchange (PLEX) has been considered as a therapeutic option when standard immunosuppressive treatments fail to control acute attacks. However, there is a growing interest in exploring the effectiveness of PLEX as a first-line therapy in NMOSD attacks, particularly to minimize disability progression and improve patient outcomes. Materials and Methods: In this retrospective cohort study, we included 40 patients diagnosed with acute NMOSD attacks. These patients were divided into two groups: Group A (n=20) received PLEX as their initial treatment, while Group B (n=20) received standard immunosuppressive therapy as per established guidelines. Patient selection criteria were based on clinical presentation, lesion localization, and the severity of symptoms. In Group A, PLEX sessions were initiated within seven days of symptom onset, with each patient undergoing a total of five exchanges over two weeks. In contrast, Group B received high-dose intravenous corticosteroids followed by maintenance immunosuppressive therapy. Results: Our findings indicate that patients in Group A, who received PLEX as a first-line therapy, experienced a more substantial reduction in Expanded Disability Status Scale (EDSS) scores compared to those in Group B, who underwent standard immunosuppression. Group A demonstrated an average improvement of -2.6 in EDSS scores, while Group B exhibited a mean improvement of -0.9. Conclusion: The outcomes of this study suggest that early administration of PLEX as a first-line therapy for acute NMOSD attacks may lead to superior clinical improvement compared to standard immunosuppression. These results underscore the potential of PLEX to mitigate disability progression and enhance patient outcomes in NMOSD. Nonetheless, it is imperative to conduct further prospective investigations to validate these findings and establish PLEX as a viable first-line treatment option for NMOSD attacks.