Purpose: This study was carried out to evaluate the bone tissue reactions to TotalFill Bioceramic (BC) and Zinc oxide eugenol (ZOE) sealers in gamma-irradiated rats. Materials and methods: In this study, round osseous bone defects were produced in the tibia of 48 male Albino rats (weighing120–150g). Group 1: 9 control non-irradiated rats, Group 2: 9 control irradiated rats, and Group 3: 30 irradiated rats in which the surgical cavities were filled with TotalFill sealer in the right tibia and ZOE in the left tibia. The assigned animals were euthanized on 7, 14, and 28 days. For histopathological examination, tissue sections stained with H & E were examined by a light microscope. Results: At 7 days, the inflammatory response of all studied groups (1, 2, and 3) showed no significant differences (p-0.092). The inflammatory response significantly decreased from 14 to 28 days in all groups, virtually disappeared in the non-irradiated group whilst intense inflammatory infiltrate was still observed in 40% of ZOE group samples with a significant difference between TotalFill vs. ZOE sealer (p- < 0.009). Bone tissue at 14 days showed severe resorption in many areas in irradiated animals that reversed at 28 days. In group 3 treated with TotalFill sealer, fiber condensation was observed in surgical cavity at 14 days which was replaced by trabeculae of bone tissue at 28 days while this event was focal in ZOE sealer. Conclusion: TotalFill sealer proved to be more compatible and has some repair potential than ZOE sealer in irradiated animals