This study developed calcium phosphate bone substitutes and their microstucture and in vitro cell response were evaluated in comparison with commercial hydroxyapatite (HA). HA powder was ball-milled and then sintered to transfer into the calcium phosphate bulks (CPB). The density, hardness, and microstructure of the CPB were investigated. The viability and proliferation of MG63 osteoblast-like cells on the commercial HA and the CPB were evaluated. The x-ray diffraction confirmed that the CPB consisted of α-tricalcium phosphate (α-TCP), CaO, and HA. The hardness, density, and α-TCP-to-HA ratio of the CPB decreased when increasing the sintering duration. Cell tests demonstrated that the CPB exhibited an earlier cell-spread response than the commercial HA. This study demonstrated that a phase transformation of HA into α-TCP and CaO was achieved by sintering. The cell tests indicated that the CPB has favorable in vitro cellular performance, which implied that it presented potential as bone substitute.