Ischemic stroke is the main cause of long-term disability and death worldwide. Studies have pointed out that antidepressants not only can be used to treat depression, but also promote nerve regeneration, nerve plasticity, and recovery of nerve function after stroke. Some evidences indicated that antidepressants have beneficial effects on ischemic stroke. At the same time, there are also risks in treatment process. The mechanisms of the effects of antidepressants on ischemic stroke are complicated and rarely reported. This review summarizes the roles of antidepressants in patients and animal models of stroke, the possible mechanisms of antidepressants against brain injury induced by stroke, and the risks and challenges of antidepressants treatment in patients with ischemia.