There are urgent demands for satisfactory antibacterial activity and mechanical properties of bone scaffolds. In this study, zinc oxide whisker (ZnOw) was introduced into calcium sulfate/bioglass scaffolds. Antimicrobial behavior was analyzed using Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). The results showed that the scaffolds presented a strong antibacterial activity after introducing ZnOw, due to the antibacterial factors released from the degradation of ZnO. Moreover, ZnOw was also found to have a distinct reinforcing effect on mechanical properties. This was ascribed to whisker pull-out, crack bridging, crack deflection, crack branching and other toughening mechanisms. In addition, the cell culture experiments showed that the scaffolds with ZnOw had a good biocompatibility.