Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are autoimmune diseases characterized by immune-mediated damage to the central nervous system. Current treatments primarily focus on chronic immunosuppression. Immune tolerance induction offers a novel approach to restoring immune balance while minimizing systemic side effects. Central and peripheral immune tolerance mechanisms regulate autoreactive lymphocytes, ensuring immune homeostasis. Dysregulation of these pathways underpins NMOSD and MOGAD pathogenesis. Antigen-specific therapies targeting aquaporin-4 (AQP4) or myelin oligodendrocyte glycoprotein (MOG) autoantigens include peptide-based vaccines and nanoparticle delivery systems, promoting T cell anergy and regulatory T cell (Treg) expansion. Cell-based therapies utilizing ex vivo-expanded Tregs or regulatory B cells (Bregs) have shown promise in preclinical models but face challenges in clinical translation due to scalability and safety concerns. Gene-editing technologies such as CRISPR/Cas9 present opportunities to modulate immune pathways and restore tolerance, although delivery and off-target effects remain obstacles. Additionally, strategies addressing double-seronegative NMOSD, which lacks detectable autoantibodies, emphasize broad immune modulation rather than antigen specificity. While significant progress has been achieved, the transition to clinical application requires overcoming hurdles such as optimizing antigen delivery, ensuring long-term efficacy, and identifying reliable biomarkers. Advances in personalized medicine hold promise for achieving sustained remission, reducing dependency on immunosuppression, and improving patient outcomes in NMOSD and MOGAD. This review explores advancements in tolerance strategies, highlighting their potential in NMOSD and MOGAD.