We prepared porous poly(ε-caprolactone)/poly(lactic-co-glycolic acid) (PCL/PLGA) 3D scaffolds with surfaces that were modified through the co-precipitation of calcium phosphate (CAP) with binary drug components, including risedronate (RSD) and hyaluronic acid (HyA). The 3D porous biodegradable PCL/PLGA scaffolds were fabricated by sintering microspheres prepared with a 30/70 PCL/PLGA blend. The co-precipitation of the CAP coating with binary drug components significantly enhanced the proliferation and differentiation of rat mesenchymal stem cells (rMSCs) on the scaffolds. Although the presence of both HyA and RSD positively improved proliferation and differentiation, HyA and RSD were more effective on osteoblastic proliferation and differentiation, respectively. These results strongly demonstrate that the drug effects on osteoblastic responses were closely interconnected. The two drugs affect rMSCs behavior in a concentration-dependent manner, requiring a balance between proliferation and differentiation for optimal bone regeneration. We expect this surface modification technique could potentially be utilized for the fabrication of functionalized biodegradable scaffolds and delivery of drug mixtures.