Calcium oscillations are induced by different stresses. Calcium-dependent protein kinases (CDPKs/CPKs) are one major group of the plant calcium decoders that are involved in various processes including drought response. Some CPKs are calcium-independent. Here, we identified ZmCPK2 as a negative regulator of drought resistance by screening an overexpression transgenic maize pool. We found that ZmCPK2 does not bind calcium, and its activity is modulated likely in an oscillation manner during short time ABA treatment. Interestingly, ZmCPK2 interacts with and is inhibited by calcium-dependent ZmCPK17, a positive regulator of drought resistance, which is activated by ABA. ZmCPK17 activity exhibits opposite patterns relative to ZmCPK2 under ABA treatment, and could prevent the nuclear localization of ZmCPK2 when co-expressed. ZmCPK2 interacts with and phosphorylates ZmYAB15, a negative transcriptional factor for drought resistance. Our results suggest that drought stress-induced Ca2+ can be decoded by corresponding CPK17 likely in an oscillation manner, thereby promoting plant adaptation to water deficit.