Background/Aim Denosumab is a human monoclonal immunoglobulin G2 antibody developed from the ovarian cells of Chinese hamsters. We aimed to histomorphometrically and radiologically evaluate the effects of xenografts used with local denosumab on the healing of defect sites using rabbit skulls. Materials and Methods Two 10-mm diameter critical-size defects were created in 16 rabbits. The defect areas were filled with xenografts and xenograft + 3 mg denosumab in the control and denosumab groups (DEN), respectively. We evaluated new bone, residual graft, soft tissue areas, and bone volume in 4- and 8-week study groups. Results Histomorphometrically, there were no statistically significant differences between groups at both 4 and 8 weeks regarding residual graft, new bone, and soft tissue area (p > 0.05). The 4-week residual graft control group values were significantly higher than the 8-week values (p < 0.05). The soft tissue area was significantly greater in the 4-week compared with the 8-week DEN group (p < 0.05). The radiologically measured total bone volume was significantly greater in the 8-week specimens than in the 4-week specimens (p < 0.05). Conclusion In this study, denosumab used locally with bone grafts, showed no direct effect on new and total bone volume.