Stroke is a leading cause of death and neurological disability worldwide. Survivors of ischemic stroke usually suffer from impairment in motor function, visual field defect, speech disorders and depression. Cerebral levels of several neurotransmitters such as dopamine, 5-hydroxytriptamine (5-HT) or serotonin, norepinephrine (NE) and glutamate alter during ischemia and contribute to the pathophysiology of cerebral ischemia. The overall effect of serotonin in cerebral ischemia is still unclear but there are evidences that enhancement of serotonin activity in the hippocampus exerts protection against neuronal damage after ischemia. Besides, several studies showed that selective serotonin reuptake inhibitors (SSRIs), serotonin/norepinephrine reuptake inhibitors (SNRIs) and serotonin agonists reduced cerebral infarct size and improved functional recovery after stroke. There are different mechanisms that may explain the neuroprotective effect of SSRIs such as fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram and escitalopram in cerebral ischemia. They exert antioxidant, antiapoptotic and anti-inflammatory activities which are responsible for their effectiveness in stroke. In this review, we will discuss in detail the role of serotonin in ischemia and the proposed mechanisms of the neuroprotective role of SSRIs in stroke.