BACKGROUND Risedronate is a bisphosphonate with poor oral absorption. An extremely hydrophilic molecule that has a high affinity for bone, risedronate also inhibits the farnesyl diphosphate synthase enzyme, inhibiting osteoclastic activity and reducing bone turnover and resorption. Autogenous bone grafts contain osteogenic cells and osteoinductive factors that are essential for bone regeneration and are therefore considered the gold standard. Thus, this study aimed to investigate the impact of local risedronate administered with autogenous bone grafts on the healing of defects in rabbit skulls using histological, histomorphometric, immunohistochemical, and three-dimensional radiological methods. METHODS Two 10-mm-diameter critical-size defects were created in 16 rabbits and filled with autogenous bone graft and autogenous bone graft + 5 mg risedronate in the control (C) 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 There were no statistically significant differences in bone graft, new bone, or soft tissue area between the groups at 4 weeks (p > 0.05). At 8 weeks, the new bone area was significantly higher in the RIS group than in the C group (p < 0.05). The h scores obtained from sialoprotein and osteopontin did not differ significantly between the groups (p > 0.05). The radiologically measured total bone volume was significantly higher in the RIS group than in the C group at both time points (p < 0.05). CONCLUSIONS In this study, risedronate enhanced the osteoconductive properties of autogenous bone grafts and rapidly created better-quality bone. This could improve future patient outcomes.