To investigate the influence of various nickel-titanium (Ni-Ti) files on debris extrusion during the retreatment of teeth with simulated lateral root perforation, focusing on root resorption. Sixty human mandibular premolar teeth were divided into groups with and without perforation and further subdivided based on the retreatment technique. Lateral root perforations were created in one group (Group 1), while the other group had no perforations (Group 2). Two retreatment techniques were compared: Remover (RE)+One RECI (OR) and ProTaper Universal Retreatment (PTUR)+WaveOne Gold (WOG). The weight of the extruded debris was determined. The time of both retreatment procedures was measured. Statistical analyses were performed using a two-way analysis of variance (ANOVA) test (P < 0.05). Teeth with simulated lateral root perforation exhibited higher extrusion of debris during retreatment. In both groups, RE+OR files led to more extruded debris than PTUR+WOG files. However, this difference was statistically significant in Group 2 (P < 0.001). Compared to PTUR+WOG files, RE+OR files showed a statistically significant longer time to remove obturation material (P < 0.001). Perforated teeth exhibited significantly higher debris extrusion. While both file systems demonstrated similar debris extrusion in perforated teeth, the RE+OR files significantly increased debris extrusion in non-perforated teeth compared to the PTUR+WOG files.