Ischemic stroke is a common disease with a high disability rate and mortality, which brings heavy pressure on families and medical insurance. Nowadays, the golden treatments for ischemic stroke in the acute phase mainly include endovascular therapy and intravenous thrombolysis. Some drugs are used to alleviate brain injury in patients with ischemic stroke, such as edaravone and 3-n-butylphthalide. However, no effective neuroprotective drug for ischemic stroke has been acknowledged. 2-Oxoglutarate-dependent dioxygenases (2OGDDs) are conserved and common dioxygenases whose activities depend on O₂, Fe²⁺, and 2OG. Most 2OGDDs are expressed in the brain and are essential for the development and functions of the brain. Therefore, 2OGDDs likely play essential roles in ischemic brain injury. In this review, we briefly elucidate the functions of most 2OGDDs, particularly the effects of regulations of 2OGDDs on various cells in different phases after ischemic stroke. It would also provide promising potential therapeutic targets and directions of drug development for protecting the brain against ischemic injury and improving outcomes of ischemic stroke.