Mucopolysaccharidosis IVA (MPS IVA) results from deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), leading to progressive keratan sulfate accumulation, and current treatments have limited efficacy. Although adeno-associated virus (AAV) gene therapy can restore systemic enzyme activity, immune responses to the transgene and viral capsid restrict durability and prevent vector re-administration. We evaluated a combined strategy of antigen-specific oral immune tolerance and sequential AAV serotype delivery. Neonatal MPS IVA mice received a mixture of three immunodominant GALNS-derived T- and B-cell epitopes on alternate days for 20 days, followed by AAV9 at 4 weeks and redosing with either AAV9 or AAV8 at 10 weeks. Peptide-treated tolerized MPS IVA mice showed a 2–3-fold increase in circulating GALNS activity after the first dose and a 7–8-fold increase after redosing, whereas non-tolerized MPS IVA mice developed anti-GALNS antibodies that reduced enzyme levels. No cross-reactive neutralizing antibodies were detected between AAV9 and AAV8. Peptide-treated mice showed normalization of plasma and hepatic keratan sulfate (KS) and significant improvements in skeletal and cardiac histopathology, with the greatest benefit in the peptide-treated AAV9→AAV8 group. These findings demonstrate that oral immune tolerance enables safe AAV re-administration, enhances systemic enzyme bioavailability, and improves tissue correction, supporting a clinically translatable approach for durable treatment of MPS IVA.