Previous study has indicated that chronic treatment with lithium protects brain against ischemic injury by reducing apoptotic death. To investigate whether lithium improves the behavioral disorder induced by transient global cerebral ischemia, we examined the effects of lithium treatment on the performance of rats in a set of behavioral tests, i.e. beam balance, elevated plus maze (EPM), open field and Morris water maze. Our results showed that lithium attenuated the worse general ‘well-being’ and the worse performance in beam balance, and hyperactivity in EPM and open field, including increased open arm entries, time spent in the open arms, squares crossed, rearing and grooming over 7 days after 15 min ischemia, which were induced by four-vessel occlusion in Sprague–Dawley rats. Moreover, lithium improved the injured spatial learning and memory ability in Morris water maze at post-ischemic days 8 and 9. Histological analysis displayed that it decreased obviously cell death in hippocampal CA1 region. Our study further confirmed the protective role of lithium in the ischemia-reperfusion injury and suggested that lithium might be a helpful therapeutic approach to the treatment of stroke combining with other neuroprotective agents.