AIM: To evaluate the effects of the combination of ketamine (KT) and N-acetylcysteine (NAC) on damage following cerebral ischemia/reperfusion in ICR mice. METHODS: Male ICR mice were randomly divided into seven groups: Sham group, NS (saline 0.1 ml·kg -1 ) group, KT (15 mg·kg -1 ) group, NAC (75 mg·kg -1 ) group, NAC+KT (75+15 mg·kg -1 ) group. (1) ICR mice underwent two hours cerebral ischemia by transient right middle cerebral artery occlusion (tMCAO) and followed 6 h and 24 h reperfusion. Then brains were prepared for the determination of the infarction volume. Before the death, neurological deficits were scored. (2) ICR mice subjected to five minutes ischemia by two common carotid arteries occlusion (2-VO) and followed 0.5 , 2 and 6 h reperfusion. Brains were prepared for the determination of the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and the content of MDA. RESULTS: (1) tMCAO produced severe neurological deficits, decreased the average score and brought about large infarction volume. KT, NAC showed the improvement of the average score and reduced infarction volume to some extent, and KT+NAC improved significantly. (2) The content of the MDA, the activities of GSH-Px and SOD in 2-VO mice deteriorated sharply, KT, NAC reduced the content of the MDA, enhanced the activities of GSH-Px and SOD, NAC+KT significantly ameliorated the levels of MDA, increased the activity of SOD and GSH-Px. CONCLUSION: The damage of cerebral ischemia/reperfusion leads to the decrease of neurological score, the increase of infarction volume, the reduction of activities of SOD and GSH-Px and the elevation of MDA. KT and NAC partly relieve the damage, and NAC and KT in combination attenuates the damage more effectively.