Submergence stress represents a serious threat to the yield and quality of maize because it can lead to oxygen deficiency and the accumulation of toxic metabolites. However, the mechanisms by which maize resists the adverse effects of submergence stress have yet to be fully elucidated. Here, we cloned a gene from maize Balem (Barley aleurone and embryo), ZmB12D, which was expressed at significant levels in seed embryos during imbibition and in leaves under submergence stress. Subcellular localization analysis indicated that the ZmB12D protein was localized in the mitochondria. The overexpression of ZmB12D in increased the tolerance of Arabidopsis to submergence stress, probably due to a reduction in the levels of malonaldehyde (MDA), the increased activity of antioxidant enzymes (SOD, POD and CAT), enhanced electron transport by coordinating the expression of non-symbiotic hemoglobin-2 (AHb2) and Fe transport-related (AtNAS3) genes (mediating Fe and oxygen availability) and also modulated the anaerobic respiration rates through upregulated the AtPDC1, AtADH1, AtSUS4 genes under submergence. Yeast one-hybrid (Y1H) and transient transactivation assays demonstrated that ZmWRKY70 bound to the ZmB12D promoter and activated ZmB12D. Collectively, out findings indicate that ZmB12D plays an important role in the tolerance of maize to submergence stress. This research provides new insights into the genetic improvement of maize with regards to submergence tolerance.