Background: To examine the effects of local risedronate application with xenografts on healing of rabbit skull defects using histological, histomorphometric, immunohistochemical, and three-dimensional radiological methods. Methods: Two critical-sized defects with a diameter of 10 mm were created in 16 rabbits and filled with xenogenic bone graft and xenogenic bone graft + 5 mg risedronate in the control I and risedronate (RIS) groups, respectively. Residual graft, new bone, soft tissue areas, and bone volume were evaluated in the 4- and 8-week study groups. Results: In both the 4- and 8-week samples, the RIS group samples had significantly higher mean new bone area values than the C group (p < 0.05). In both groups, the values for the new bone area were significantly higher in the 8-week-old samples than in the 4-week-old samples (p < 0.05). The h scores obtained for sialoprotein and osteopontin did not differ significantly between the groups at either time point (p > 0.05). The results of radiological evaluation showed that the bone density value was significantly higher in the C group than in the RIS group at either time point (p < 0.05). Conclusions: Although this study aimed to demonstrate the effect of risedronate on the osteoconductive properties of xenografts when applied locally, targeted results could not be achieved.