Objective: In this study, we aimed to investigate the effectiveness of the use of polypropylene mesh and platelet-rich fibrin (PRF) in nasal septal perforation (NSP) repair. Study Design: Prospective experimental study. Setting: Laboratory. Methods: Twenty-four adult male New Zealand rabbits were used in our study. In all subjects, a 10 × 10 mm perforation was created in the septum. The subjects were divided into 3 equal groups according to the different methods used in perforation closure. The bilateral mucosal flap was used in the control group, polypropylene mesh + bilateral mucosal flap in the mesh group, and polypropylene mesh + bilateral mucosal flap + PRF in the mesh + PRF group. Results: NSP treatment success rate was found to be significantly higher in the mesh (4/6, 66.7%) and mesh + PRF (6/6, 100%) groups compared to the control group (0/6, 0%). Re-epithelialization score was higher in the mesh + PRF group and the control group compared to the mesh group. While the necrosis, neutrophil, and abscess scores were highest in the mesh group, they were similar to the control group in the mesh + PRF group. Conclusions: While polypropylene mesh significantly increases the success rate in NSP repair, it causes severe inflammatory responses. However, when polypropylene mesh is combined with PRF, it both increases the rate of perforation closure and significantly reduces the complications associated with the use of mesh.