Maize (Zea mays) is highly susceptible to waterlogging stress, which reduces both the yield and quality of this important crop. However, the molecular mechanism governing waterlogging tolerance is poorly understood. In this study, we identify a waterlogging- and ethylene-inducible gene ZmEREB179 that encodes an ethylene response factor (ERF) localized in the nucleus. Overexpression of ZmEREB179 in maize increases the sensitivity to waterlogging stress. Conversely, the zmereb179 knockout mutants are more tolerant to waterlogging, suggesting that ZmEREB179 functions as a negative regulator of waterlogging tolerance. A transcriptome analysis of the ZmEREB179-overexpressing plants reveals that the ERF-type transcription factor modulates the expression of various stress-related genes, including ZmEREB180. We find that ZmEREB179 directly targets the ZmEREB180 promoter and represses its expression. Notably, the analysis of a panel of 220 maize inbred lines reveals that genetic variations in the ZmEREB179 promoter (Hap2) are highly associated with waterlogging resistance. The functional association of Hap2 with waterlogging resistance is tightly co-segregated in two F