This paper introduces a novel bone-regenerative scaffold that is based on the systematic combination of porous polymer microspheres, nano-hydroxyapatite, and bone morphogenetic protein-2 (BMP-2), where each component was rationally incorporated to express its intrinsic activity in bone tissue formation. Poly(lactide-co-glycolide) (PLGA) microspheres, with interconnected pore structures, were fabricated by a gas-forming method in a water-in-oil-in-water double emulsion and solvent evaporation process. Polyphosphate-functionalized nano-hydroxyapatite (PP-n-HAp) was employed as a main component and was immobilized on the pore surface of the PLGA microspheres to controllably incorporate and release BMP-2. The surface polyphosphate functionalities of PP-n-HAp enabled the stable chemical immobilization of nano-hydroxyapatite (n-HAp) on the amine-treated pore surface of the PLGA microspheres. Field-emission scanning electron microscopy (FE-SEM) and X-ray photoelectron spectroscopy (XPS) confirmed the nano-level exposure of n-HAp on the pore surface of the PLGA microspheres. BMP-2 with a positive charge was bound at a high efficiency onto the anionic phosphates of surface-immobilized PP-n-HAp and was controllably released for approximately 1 month. The release rate was manipulated by adjusting the amount of loaded BMP-2. The osteogenic differentiation and proliferation of human adipose-derived stem cells (hADSCs) within the n-HAp/BMP-2-incorporated microspheres were monitored in a dynamic 3D cell culture system. Histological, immunohistochemical, and quantitative real-time polymerase chain reaction (PCR) analyses showed that the PP-n-HAp-immobilized surface promoted cell adhesion/proliferation and osteoconduction. With its osteoinductive property, the sustained release of BMP-2 further enhanced the bone tissue regenerative activity of the porous microspheres.