Previous studies utilizing α-melanocyte-stimulating hormone (α-MSH) or the synthetic analog [Nle⁴, <i>D</i>-Phe⁷] α-MSH have reported beneficial effects in animal models of ischemic stroke, with the latter studies suggesting melanocortin receptor subtype-4 (MC4R) activation as a protective mechanism. The present study directly addresses the hypothesis that MC4R activation may ameliorate ischemic brain injury by assessing the efficacy of a novel small molecule MC4R agonist RY767, administered in a pharmacokinetically guided and pharmacologically validated dosing regimen, in a rat stroke model of transient middle cerebral artery occlusion (tMCAO). Male Wistar rats were subjected to 90-min tMCAO followed by 72 h of reperfusion. Treatments were i.p. pretreatment with MK-801 (15 min prior to occlusion, positive control), or combined i.v. and p.o. daily administrations of vehicle, dextrose (negative control) or RY767 in blinded fashion initiated 2 h after occlusion. Infarct volume in MK-801-treated rats (158.7 ± 22.3 mm³) was reduced significantly compared to vehicle infarct volume (243.4 ± 12.5 mm³), whereas infarct volumes in dextrose- (224.3 ± 16.5 mm³) and RY767- (262.1 ± 19.2 mm³) treated rats did not differ from vehicle infarct volume. These results indicate that selective MC4R activation provides no significant neuroprotection, as reflected by infarct volume, in a rat stroke model utilizing a 90-min ischemic insult.