Findings: We describe a septal perforation repair technique aimed for moderate to large perforations, which involves a unilateral transpositional/rotational flap utilizing lateral nasal wall and inferior turbinate (IT) mucosa and a contralateral underlay porcine small intestinal submucosa mesh. Meaning: The addition of IT mucosa as part of the unilateral lateral nasal wall mucoperichondrium/periosteal flap combined with a contralateral acellular matrix underlay optimizes the repair of larger perforations. The underlay acellular matrix acts as a scaffold for the regeneration of healthy mucoperichondrium akin to a tympanoplasty repair and reduces donor site morbidity.