Preclinical ischemic stroke studies extensively utilize the intraluminal suture method of middle cerebral artery occlusion (MCAo). General anesthesia administration is an essential step for MCAo, but anesthetic agents can lead to adverse effects causing death and making a considerable impact on inducing cerebral ischemia. The purpose of this study was to comparatively assess the effect of isoflurane and xylazine on transient cerebral ischemia in a mouse model of MCAo. Twenty animals were randomly divided into four groups: sham group (no MCAo), control group (MCAo under isoflurane, no agent till reperfusion), isoflurane group (MCAo under isoflurane continued till reperfusion), xylazine group (MCAo under isoflurane, and administration of xylazine till reperfusion). The survival rate, brain infarct volume, and neurologic deficits were studied to assess the effect of isoflurane and xylazine on the stroke model. Our results showed that the body weight showed statistically significant change before and 24 h after surgery in the control and Isoflurane groups, but no difference in the Xylazine group. Also, the survival rate, brain infarct volume, and neurologic deficits were slightly reduced in the isoflurane group at 24 h after reperfusion injury. However, the xylazine and control groups showed similar BIV and neurologic deficits. Interestingly, a high survival rate was observed in the xylazine group. Our results indicate that the modified method of inhalation anesthetics combined with xylazine can reduce the risk of mortality and develop a reproducible MCAo model with predictable brain ischemia. In addition, extended isoflurane anesthesia after MCAo is associated with the risk of mortality.