The development of cognitive impairment in sepsis is associated with neurotoxic effects caused by oxidative stress. We have assessed the effects of acute and extended administration of guanosine (GUA) on brain oxidative stress parameters and cognitive impairment in rats submitted to sepsis by cecal ligation and perforation (CLP). To achieve this goal, male Wistar rats underwent either sham operation or CLP with GUA. Rats subjected to CLP were treated with intraperitoneal injection of GUA (8 mg/kg after CLP) or vehicle. Twelve and 24 h after CLP, the rats were sacrificed, and samples from brain (hippocampus, striatum, cerebellum, prefrontal cortex and cortex) were obtained and assayed for thiobarbituric acid reactive species (TBARS) formation and protein carbonyls. On the 10th day, another group of rats was submitted to the behavioral tasks. GUA administration reduced TBARS and carbonyl levels in some brain regions between 12 and 24 h after CLP, and ameliorated cognitive impairment evaluated 10 days after CLP. Our data provide the first experimental demonstration that GUA was able to reduce the consequences of CLP-induced sepsis in rats, by decreasing oxidative stress parameters in the brain and recovering the memory impairment.