The microstructural, in vitro and in vivo properties of the microwave-synthesized samples were investigated using the optical microscope, scanning electron microscope, X-ray diffraction, differential scanning calorimeter, contact angle goniometer, cell cytotoxicity assay, and chick chorioallantoic membrane (CAM) model in the study. When the calcium sulfate dihydrate (CSD) precursor underwent microwave irradiation treatment at temperatures between 100°C and 160°C, the crystal morphologies and crystalline structures were transformed from (tablet-like CSD (monoclinic)) → (tablet-like CSD (monoclinic) + long column α-calcium sulfate hemihydrate (α-CSH, hexagonal)) → (long column CSD (monoclinic) + short column α-CSH (hexagonal)) → (uniform short column α-CSH (hexagonal)). The high-purity α-CSH with uniform short column crystals around 10 μm in length can be synthesized at 160°C for 10 minutes and exhibits a higher hydrophilic feature in blood. Moreover, the cell cytotoxicity assay indicated that the microwave-synthesized samples possessed well biocompatibility. In vivo results also demonstrated that the microwave-synthesized α-CSH not only induces angiogenesis formation but also facilitates osteogenesis. Therefore, the microwave-synthesized α-CSH is a promising bone graft substitute that can be applied in dental and orthopedic fields.