Summary Aim Insulin‐like growth factor I (IGF‐I) is a neuroprotective agent in animal models of ischemic stroke. The purpose of this study was to determine whether systemically injected IGF‐I exerts its neuroprotective action by binding to IGF‐I receptors in the brain after crossing the blood–brain barrier, or via peripheral effects. Methods To differentiate the central effects of IGF‐I from systemic effects, ischemic stroke was induced in conscious male Wistar Kyoto rats by the injection of endothelin‐1 adjacent to the middle cerebral artery in the right hemisphere, while either the IGF‐I receptor antagonist JB‐1 or vehicle was introduced into the right lateral ventricle. Results Intravenous injection of recombinant human (rh)IGF‐I resulted in 50% reduction in infarct size, which was counteracted by the central administration of JB‐1. Furthermore, rhIGF‐I was detected in both the ischemic and nonischemic hemisphere. Conclusions Systemically injected rhIGF‐I passes the blood–brain barrier and protects neurons via IGF‐I receptors in the brain in rats with an ischemic stroke.