Autologous dentin is frequently used in guided bone regeneration due to its osteoinductive properties, which come from its similarity to native bone. On the other hand, the xenogeneic bone biomaterial Cerabone® serves as a biocompatible, but hardly resorbed biomaterial. During bone healing, an inflammatory, vascular, and osteogenic response occurs in which cytokines such as tumor necrosis factor-alpha (TNF-α), vascular endothelial growth factor (VEGF), and osteopontin (OPN) are released locally and systemically. The aim was to follow up the dynamics (on days 3, 7, 15, 21, and 30) of critical-sized bone defect (CSBD) healing after the implantation of bovine devitalized dentin, rat dentin, and xenogeneic bone biomaterial. For this purpose, histological and histomorphometric methods were employed. Additionally, serum concentrations of TNF-α, VEGF, and OPN were monitored in parallel to better understand the biomaterial-dependent systemic response in rats. At the last time interval, the results showed that the bone defect was bridged over in all three groups of biomaterials. The rat dentin group had the highest percentage of bone volume (BV/TV) and the least percentage of residual biomaterial (RB), which makes it the most optimal biomaterial for bone regeneration. Serum concentrations of the TNF-α, VEGF, and OPN refer to systemic response, which could be linked to intense bone remodeling between days 15 and 21 of the bone healing.