BackgroundA variety of novel monoclonal antibodies and immunosuppressant have been proved effective in treating Neuromyelitis Optica Spectrum Disorder (NMOSD). This network meta-analysis compared and ranked the efficacy and tolerability of currently used monoclonal antibodies and immunosuppressive agents in NMOSD.MethodsElectronic database including PubMed, Embase and Cochrane Library were searched for relevant studies evaluating monoclonal antibodies and immunosuppressants in patients with NMOSD. The primary outcome measures were annualized relapse rate (ARR), relapse rate, the Expanded Disability Status Scale (EDSS) score, and total adverse events (AEs).ResultsWe identified 25 studies with 2919 patients in our meta-analysis. For the primary outcome, rituximab (RTX) (SUCRA: 0.02) ranked first in reduction ARR with a significant difference compared with azathioprine (AZA) (MD – 0.34, 95% CrI – 0.55 to – 0.12) and mycophenolate mofetil (MMF) (MD –0.38, 95% CrI – 0.63 to – 0.14). Tocilizumab (SUCRA: 0.05) ranked first in relapse rate, which was superior to satralizumab (lnOR – 25.4, 95% CrI – 74.4 to – 2.49) and inebilizumab (lnOR – 24.86, 95% CrI – 73.75 to – 1.93). MMF (SUCRA: 0.27) had the fewest AEs followed by RTX (SUCRA: 0.35), both of which showed a significant difference compared with AZA and corticosteroids (MMF vs AZA: lnOR – 1.58, 95% CrI – 2.48 to – 0.68; MMF vs corticosteroids: lnOR – 1.34, 95% CrI – 2.3 to – 0.37) (RTX vs AZA: lnOR – 1.34, 95% CrI – 0.37 to – 2.3; RTX vs corticosteroids: lnOR – 2.52, 95% CrI – 0.32 to – 4.86). In EDSS score, no statistical difference was found between different interventions.ConclusionRTX and tocilizumab showed better efficacy than traditional immunosuppressants in reducing relapse. For safety, MMF and RTX had fewer AEs. However, studies with larger sample size on newly developed monoclonal antibodies are warranted in the future.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00415-023-11641-1.