Due to the low strength and high brittleness of 45S5 Bioglass, it is still a great challenge for the three-dimensional porous 45S5 Bioglass to treat mechanically required loaded bone defects. Therefore, 45S5 Bioglass-derived bioactive glass-ceramic (BGC) porous scaffolds were fabricated at a low temperature sintering condition with and without the addition of 4% low-melting ZnO/BO (ZB) bioactive glass as a reinforcing agent and using 350- or 500 μm paraffin microspheres as a porogen. The pore structure characterization for the scaffolds indicated that the scaffolds containing 4% ZB had very good macroporous structures of ∼313 and ∼448 μm in pore size and over 70% porosity with appreciable strength (>15 MPa), which was about four times higher than that those manufactured without ZB and with 350 μm porogen scaffolds. The open porosity was decreased with the addition of 4% ZB but the interconnected pore percentage (>50 μm) was increased with increasing the porogen size from 350 to 500 μm. In vivo investigations revealed that the stronger scaffolds containing 4% ZB and 500 μm porogen were particularly beneficial for osteogenic capacity in critical size femoral bone defects, accompanied with an accelerated bone ingrowth (6-18 weeks) and the material itself experiencing mild resorption. In contrast, both the scaffolds with smaller pore sizes exhibited a low level of new bone ingrowth (<32%) after 6-12 weeks implantation. These results suggest a promising application of such 45S5 Bioglass-derived BGC scaffolds in a clinical setting, especially for mechanically loaded bone defects.