This study aims to assess the biocompatibility and inflammatory response of four commercially available bone graft substitutes using an in vivo murine air pouch model. The substitutes included coralline hydroxyapatite in its pure form, known for its osteoconductive properties, and three other products with both osteoconductive and osteoinductive properties. Over a 14-day implant period, samples were collected from the pouches to extract mRNA markers for inflammation and to analyze cellular responses through various histological characteristics. The findings indicate that while autogenous bone grafts are preferred due to reduced morbidity risks, bone substitutes can be effective yet raise safety concerns. Hematology and polymerase chain reaction analyses revealed that high demineralized bone matrix to carrier ratios correlate with elevated inflammatory responses. Coralline hydroxyapatite showed relatively mild inflammation compared to other substitutes. These results underscore the importance of considering both efficacy and safety when selecting bone grafting methods. Further studies are necessary to enhance treatment outcomes and minimize morbidity.