<p>Pediatric-acquired demyelinating syndromes, including multiple sclerosis (MS), aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) constitute distinct entities arising during critical periods of neurodevelopment. Early and effective treatment is therefore crucial to prevent long-term disability. Converging evidence supports a central role of B-cells in central nervous system autoimmunity, extending beyond antibody production to include antigen presentation, cytokine production, and T-cell modulation. B-cell-depleting anti-CD20 therapies are increasingly used in this setting, but the strength and consistency of evidence differ substantially across diseases and individual drugs. Available data indicate that anti-CD20 treatment provides significant suppression of relapses and MRI activity in pediatric MS. Rituximab, although used off-label, has shown a significant reduction in annualized relapse rates and inflammatory MRI activity across observational cohorts. Ocrelizumab has the most advanced pediatric evidence among approved anti-CD20 agents, including dose-selection data from OPERETTA I and comparative Phase 3 data from OPERETTA II, where it reduced MRI activity compared with fingolimod and showed sustained B-cell depletion. In contrast, evidence for ofatumumab in pediatric MS remains limited to very small case series, although dedicated pediatric trials are ongoing. No pediatric data are currently available for ocrelizumab or ofatumumab in AQP4+NMOSD or MOGAD. In pediatric AQP4+NMOSD, rituximab remains the best-supported anti-CD20 option, with observational studies showing relapse reduction and a close relationship between CD19-positive B-cell repopulation and breakthrough disease activity. In relapsing MOGAD, responses to rituximab are heterogeneous: some cohorts report reduced relapse frequency during sustained B-cell depletion, whereas others describe continued relapses despite treatment, suggesting that pathogenic mechanisms beyond CD20-positive B-cells, including long-lived plasma cells or non-B-cell immune pathways, may contribute to disease activity. Across pediatric cohorts, anti-CD20 therapies are generally well tolerated. Infusion-related reactions are common but usually mild, infections are typically non-severe, and hypogammaglobulinemia, leukopenia, delayed neutropenia, vaccine-response attenuation, and early B-cell repopulation require individualized monitoring. Upcoming trials of ofatumumab, ublituximab, and rituximab-based strategies in MOGAD will be critical to refine pediatric dosing, define biomarkers of treatment durability, and establish age-specific safety surveillance for the developing immune system. This review summarizes knowledge on B-cell maturation in early life and anti-CD20 treatment outcomes in pediatric patients with these conditions. Safety and tolerability considerations, optimal timing of therapy, and remaining gaps in evidence are also explored, highlighting the need for age-specific biomarkers and prospective studies to better define individualized treatment strategies and to clarify long-term consequences of B-cell-depleting therapies in children.</p>