Glycogen synthase kinase 3 (GSK3)-like kinases play important roles in stress responses in plants. However, the mechanism of GSK3-like kinases in drought-induced antioxidant defense is not clear. In this study, we discovered that the GSK3-like kinase SHAGGY-like kinase 1 (ZmSK1) negatively regulates drought tolerance by inhibiting antioxidant defense in maize (Zea mays). Then, we determined that cysteine-rich polycomb-like protein 2 (ZmCPP2) interacts with ZmSK1 and enhances maize drought tolerance by inducing antioxidant defense. ZmCPP2 is phosphorylated at Ser-250 by ZmSK1, which is dependent on ZmSK1 kinase activity and attenuates maize drought tolerance. Furthermore, ZmCPP2 directly binds to the promoter of the superoxide dismutase (SOD) gene ZmSOD4, encoding an antioxidant defense enzyme, and activates its expression. ZmSK1 phosphorylating ZmCPP2 at Ser-250 represses the binding of ZmCPP2 to the ZmSOD4 promoter. Taken together, our results indicate that the phosphorylation of ZmCPP2 by ZmSK1 results in decreased SOD activity and thus reduces drought tolerance in maize. These findings reveal a mechanism of GSK3-like kinases regulating antioxidant defense in the drought stress response.