Crocus sativus L. has been used throughout the world in traditional medicine as a treatment for neurological disorders such as depression. Growing attention is currently being paid to the use of neuroprotective agents in ischemic strokes.This study assed the effect of saffron as a neuroprotective natural product in cerebral ischemia in human.Patients with acute ischemic stroke were randomly allocated to receive either routine stroke care (control group, n = 20) or routine care plus aqueous extract of saffron capsule (200 mg/day) (saffron-treated group, n = 19). Both groups were monitored during their four-day hospital stay and the three-month follow-up period. The groups were compared in terms of short- and long-term effects of saffron capsules using the National Institute of Health Stoke Scale (NIHSS), Barthel Scale, and serum neuron specific enolase (NSE), Brain-derived neurotrophic factor (BDNF), S100 levels.Based on the NIHSS, the severity of stroke during the first four days was significantly lower in the saffron-treated group than in the control group (P < 0.05). Compared to the levels on the first day, serum NSE and s100 levels were significantly decreased and BDNF concentration was increased in the saffron-treated group on the fourth day. Also, our results showed there was a negative significant non-linear cubic regression between BDNF concentration and score of NIHSS. At the end of the three-month follow-up period, the mean Barthel index was significantly higher in the saffron-treated group than in the control group (P < 0.001).The results of this study confirmed the short and long-term neuroprotective effects of aqueous extract of saffron on ischemic stroke in humans.