Background <p>Bone healing in osteoporotic bone represents a significant clinical challenge in oral and maxillofacial surgery. The aim of this experimental study was to evaluate the effects of melatonin and vitamin E supplementation on bone healing following alloplastic graft application in cranial bone defects created under osteoporotic conditions.</p> Methods <p>A total of 35 male Wistar rats were randomly allocated into five groups. Experimental osteoporosis was induced by retinoic acid administration. Following osteoporosis induction, critical-sized cranial bone defects were created in the parietal bone. Except for the negative control group, all defects were filled with an alloplastic bone graft. Melatonin and/or vitamin E were administered systemically to the experimental groups. At the end of the experimental period, bone healing was evaluated histologically.</p> Results <p>No bone healing was observed in the negative control group, whereas mild to moderate new bone formation was detected in the graft control group. The melatonin-treated group demonstrated pronounced and high-grade bone formation. In contrast, the vitamin E-treated group did not show a significant improvement in bone healing compared to the graft control group.</p> Conclusions <p>The findings of this experimental study suggest that melatonin may have a supportive effect on bone healing following alloplastic grafting in osteoporotic bone defects. Vitamin E, either alone or in combination with melatonin, did not provide an additional benefit in terms of bone regeneration. These results provide preclinical evidence to guide the selection of biological adjunctive agents in osteoporotic bone healing.</p>