Heat generated during implant osteotomy might lead to osteonecrosis and delayed bone repair, thus resulting in impaired early osseointegration and fixation of bone-anchoring devices. In this study, we proposed to overcome heat-induced injury to bone by fabricating core-shell polymeric biodegradable microspheres encapsulating a mitogenic factor, platelet-derived growth factor (PDGF), and a differentiation factor, simvastatin, in a simultaneous or sequential release profile. Microspheres encapsulating bovine serum albumin (BSA), PDGF, simvastatin, PDGF-in-core with simvastatin-in-shell, and simvastatin-in-core with PDGF-in-shell were delivered to fill standardized osteotomy sites on edentulous ridges of rat maxillae under irrigated or non-irrigated conditions. In the absence of irrigation, significant reduction of cell viability and increase in inflammation and sequestrum formation without evidence of osteogenesis were observed. Both PDGF and simvastatin deliveries facilitated cell viability and reduced osteonecrosis. Localized osteogenesis was seen under simvastatin treatment, while generalized but primitive osteogenesis was noted in PDGF-treated osteotomy sites. In addition, sequential PDGF-simvastatin delivery further augmented osteogenesis and promoted bone maturation. The results suggested that sequential PDGF-simvastatin delivery was an effective modality to prevent heat-induced complications and facilitate bone apposition after implant osteotomy, potentially favoring the early fixation of bone-anchoring devices and oral implant osseointegration.