The CaO–M_xO_y–SiO₂–P₂O₅ (M = Zr, Mg, Sr) MBG scaffolds have been successfully prepared by the combination of polyurethane sponge and block copolymer EO₂₀PO₇₀EO₂₀ (P123) as co-templates and evaporation-induced self-assembly (EISA) process using Ca, P, Si and M sources. X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and N₂ adsorption–desorption technique were used to analyze the microstructure, pore size and morphology of these MBG scaffolds. These MBG scaffolds have the interconnected macroporous network with the pore diameter of 200–400 μm and the mesoporous wall with the mesopore size of 3–4 nm. The effects of the partial substitution of ZrO₂, MgO or SrO for CaO on the physiochemical and biological properties of the MBG scaffolds were evaluated by the mechanical strength, ion dissolution, apatite-forming ability, and proliferation, alkaline phosphatase (ALP) activity and osteogenic expression of osteoblast-like cells MC3T3-E1. The results showed that the ZrO₂-substituted MBG scaffold enhanced the mechanical strength, and exhibited a slower ion dissolution rate and more significant potential to stabilize the pH environment compared to other MBG scaffolds. The CaO–M_xO_y–SiO₂–P₂O₅ MBG scaffolds showed a good apatite-forming ability and facilitated osteoblast cells' proliferation and differentiation to different extents. In particular, the ZrO₂-substituted MBG scaffold exhibited the best biological property compared to other MBG scaffolds. Furthermore, the CaO–M_xO_y–SiO₂–P₂O₅ MBG scaffolds also had a sustained drug release property for use in local drug delivery therapy. Therefore, the CaO–M_xO_y–SiO₂–P₂O₅ MBG scaffolds have more potential for the application in bone tissue regeneration.