Waterlogging stress severely hampers plant growth and represents a major challenge to agricultural productivity. Therefore, identifying key genes involved in plant waterlogging responses and elucidating the underlying regulatory mechanisms are essential for sustaining modern agriculture. In this study, we unraveled a specific role of the maize WRKY transcription factor ZmWRKY122, which was significantly induced by waterlogging stress, in improving tolerance to waterlogging stress. ZmWRKY122 was localized to the nucleus and functioned as a transcriptional activator in vivo. Functional and physiological analyses revealed that ZmWRKY122 improved maize tolerance to waterlogging by enhancing the antioxidant defense system, thereby alleviating oxidative damage. Transcriptome and qRT-PCR analyses further demonstrated that ZmWRKY122 upregulated ZmPRX101 expression in maize roots under waterlogged conditions. A combination of yeast one-hybrid, chromatin immunoprecipitation qPCR, and electrophoretic mobility shift assays confirmed that ZmWRKY122 directly bound to the W-box motif in the ZmPRX101 promoter. Furthermore, functional analyses indicated that ZmPRX101 knockout significantly decreased maize tolerance to waterlogging by exacerbating oxidative damage. Collectively, these results demonstrate that ZmWRKY122 positively regulates ZmPRX101 to alleviate waterlogging-induced oxidative stress, thereby improving waterlogging stress tolerance in maize.