Background Biological markers of acute nerve cell damage can assist in the outcome of acute ischemic stroke, such as neuron-specific enolase (NSE) that have been tested for association with initial severity of stroke, extent of infarction, and functional outcome. Objective To determine short-term prognostic value of the biochemical marker neuron-specific enolase (NSE) in acute ischemic stroke. Methods A cohort study carried out on 37 patients with acute ischemic stroke. Data were gathered in a prepared data sheet. Initial serum NSE level was measured to the patients in the Emergency department within 6 h of the onset of stroke and another measurement after 48 h. National Institute of Health Stroke Scale (NIHSS) was held to the patients at presentation and after 28 days of stroke to determine short-term morbidity and mortality. Results Out of the 37 patients, 31 patients survived (no-death group) and 6 patients died (death group). The mean serum level of neuron-specific enolase at presentation and after 48 h was significantly higher in the death group than in the no-death group. There was a statistically significant positive correlation between neuron-specific enolase (NSE) serum level and clinical severity of stroke (NIHSS) among the patients at presentation (r = 0.737, p = 0.000). Conclusion Neuron-specific enolase (NSE) can be applied as single independent marker for prediction of mortality and short-term morbidity in ischemic stroke patients.