Excitotoxicity mediated by the N-methyl-D-aspartate receptor (NMDAR) is believed to be a primary mechanism of neuronal injury following stroke. Thus, many drugs and therapeutic peptides were developed to inhibit either the NMDAR at the cell surface or its downstream intracellular death-signaling cascades. Nevertheless, the majority of focal ischemia studies concerning NMDAR antagonism were performed using the intraluminal suture-induced middle cerebral arterial occlusion (MCAO) model, which produces a large cortical and subcortical infarct leading to hypothalamic damage and fever in experimental animals. Here, we investigated whether NMDAR antagonism by drugs and therapeutic peptides was neuroprotective in a mouse model of distal MCAO (dMCAO), which produces a small cortical infarct sparing the hypothalamus and other subcortical structures. For establishment of this model, mice were subjected to dMCAO under normothermic conditions or body-temperature manipulations, and in the former case, their brains were collected at 3-72 h post-ischemia to follow the infarct development. These mice developed cortical infarction 6 h post-ischemia, which matured by 24-48 h post-ischemia. Consistent with the hypothesis that the delayed infarction in this model can be alleviated by neuroprotective interventions, hypothermia strongly protected the mouse brain against cerebral infarction in this model. To evaluate the therapeutic efficacy of NMDAR antagonism in this model, we treated the mice with MK801, Tat-NR2B9c, and L-JNKI-1 at doses that were neuroprotective in the MCAO model, and 30 min later, they were subjected to 120 min of dMCAO either in the awake state or under anesthesia with normothermic controls. Nevertheless, NMDAR antagonism, despite exerting pharmacological effects on mouse behavior, repeatedly failed to show neuroprotection against cerebral infarction in this model. The lack of efficacy of these treatments is reminiscent of the recurrent failure of NMDAR antagonism in clinical trials. While our data do not exclude the possibility that these treatments could be effective at a different dose or treatment regimen, they emphasize the need to test drug efficacy in different stroke models before optimal doses and treatment regimens can be selected for clinical trials.