Limb-girdle muscular dystrophy type 2 (LGMDR2) is caused by loss-of-function mutations that impair the production of dysferlin, a protein critical for muscle membrane repair. Gene replacement using adeno-associated viral (AAV) vectors offers a promising approach to restore dysferlin expression. However, the limited packaging capacity of AAV vectors (~4.7 kb) prevents the delivery of the full 8.5 kb dysferlin cDNA. To overcome this limitation, we adapted the SIMPLI-GT (Split Intein-Mediated Protein Ligation for Gene Therapy) method for dysferlin. This novel technique uses the protein trans-splicing process to express large proteins by expressing two halves of the large full-length proteins with each packaged into an AAV vector. When the dysferlin N-terminal and C-terminal split intein-tagged half containing plasmids were co-delivered in cultured C2C12 myoblasts, we observed successful expression of full-length dysferlin, which was more efficient than a single plasmid expressing the complete dysferlin protein. We tested the use of myotropic AAV vectors to deliver the split dysferlin in cultured myotubes, and in vivo in the BlA/J mouse model of LGMDR2. Local intramuscular delivery and systemic intravenous delivery both efficiently restored dysferlin expression in vivo. The functionality of the restored dysferlin was assessed using injury assays, and histopathological improvements examined in BlA/J mice treated systemically with SIMPLI-GT. These studies demonstrate the utility of SIMPLI-GT for expressing functional full-length transmembrane proteins like dysferlin, opening the door for a potentially safe and effective curative therapy for LGMDR2.