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Background: Bone substitutes have been used by doctors for a long time to treat osseous abnormalities. Recently, scientists have been searching for suitable materials to replace bone. Autogenous bone grafts are considered the gold standard for osseous regeneration. However, the limited availability of intraoral sources for grafting material often requires the use of secondary donor sites. Aim: This study aims to compare a control group of standard critical bone defect models treated without any bone transplants to critical size calvarial bony defects treated with various bone replacements, including simvastatin and α-tricalcium phosphate, while analyzing the healing patterns. Materials and Methods: In this investigation, 24 Wistar Albino rats weighing 200–250 g were utilized. The study included four groups, each consisting of six rats. Group I utilized deproteinized bovine xenograft, Group II used Simvastatin (0.1 mg), Group III used Simvastatin (0.1 mg) plus TCP, and Group IV served as the untreated calvarial defects group. After eight weeks of testing, the rats were euthanized, and the calvaria were extracted, decalcified in 20% formic acid, and prepared for histological analysis. Results: The newly produced osseous tissue consisted of woven and lamellar bone, which was observed in all deformities. The mean widths of new bone development in the SIMV with α-TCP (Group III) group after XENO (Group I) and the control group with no graft implantation were 160.33 ± 16.2 µm, 110.59 ± 11.5 µm, and 50.83 ± 5.5 µm, respectively. However, these differences did not show statistical significance (p > 0.05). Conclusions: The quantity and quality of newly produced osseous tissue were comparable in α-TCP with SIMV and XENO. However, inflammatory infiltration was 8more pronounced in regions where SIMV was present alone compared to the combination group.