Ethanol consumption has well-known deleterious effects on memory. However, the mechanism by which ethanol exerts its effects on memory has received little attention, which has retarded the identification and development of effective therapeutic strategies against ethanol toxicity. The aim of this study was to explore the neuronal mechanisms underlying the protective action of curcumin, a natural polyphenolic compound of Curcuma longa, against ethanol-induced memory deficits. Adult mice were pretreated with curcumin (40 mg/kg, i.p.) before administration of ethanol (1 g/kg, i.p.) for the memory acquisition measurement, or were sacrificed 30 min later for evaluation of regional brain differences in the nitric oxide synthase (NOS) activity and nitric oxide (NO) concentration. The results showed that pretreatment with curcumin significantly ameliorated the memory deficits resulting from acute ethanol administration to mice in the novel object recognition and inhibitory avoidance tasks. Furthermore, acute ethanol treatment increased the NOS activity and NO production in brain regions associated with memory including prefrontal cortex (PFC), amygdala and hippocampus, while this enhancement was suppressed by pretreatment with curcumin. Taken together, these results suggest that the protective effects of curcumin on acute ethanol-induced memory deficits are mediated, at least in part, by suppressing NOS activity in the brain of mice. Thus, manipulation of the NOS/NO signaling pathway might be beneficial for the prevention of ethanol toxicity.