Plant growth and production are strongly affected by water deficit. Mitogen-activated protein kinase kinase kinases (MAP3Ks) are essential signaling components for responses to abiotic stress in many plants. However, the molecular mechanisms underlying their roles in drought-stress tolerance in wheat ( Triticum aestivum ) remain unclear. In this study, we identified TaMAP3K17 as a drought-induced MAP3K gene in wheat and demonstrated that it encodes a protein localized to both the plasma membrane and nucleus. TaMAP3K17 -silenced plants generated by virus-induced gene silencing (VIGS) were hypersensitive to drought stress and accumulated higher levels of reactive oxygen species (ROS) compared to the wild type. TaMAP3K17 overexpression enhanced drought-stress tolerance in transgenic wheat plants. Yeast one-hybrid and dual-luciferase reporter assays showed that TaMYB2 activates the transcription of TaMAP3K17 . Suppressing TaMYB2 expression by VIGS resulted in ROS generation and malondialdehyde accumulation in wheat under water-deficit conditions. These findings suggest that a TaMYB2–TaMAP3K17 regulatory module is involved in ROS homeostasis and drought responses in wheat.