Background: Ginsenoside Rh1, a 20(S)-protopanaxatriol with a single sugar moiety from ginseng, has benefits on the central nervous system and recently Rh1 had been reported to be effective for the Alzheimer's disease (AD). Objective: The present study was conducted to investigate the neuroprotective effects of Ginsenoside Rh1 on scopolamine-induced cognitive dysfunctions and to elucidate its underlying mechanisms of action. Methods: Rh1 (20 and 40 μmol/kg) was administered intraperitoneally to mice for 28 days, and scopolamine (0.75 mg/kg) was injected intraperitoneally for 10 days to induce memory deficit. Memory-related behaviors were evaluated using object location recognition (OLR) experiment, novel object recognition (NOR) test, Morris water maze (MWM) test and passive avoidance (PA) task. Cholinergic system function and oxidative stress activities were measured in the hippocampus. The expression levels of CREB, Egr-1, c-Fos and c-Jun were also measured in the hippocampus. Results: Rh1 administration could improve the cognitive performance of scopolaminetreated mice in the object location recognition, the novel object recognition, the Morris water maze and the passive avoidance tests. And Rh1 significantly enhanced cholinergic system function and suppressed oxidative stress level in the hippocampus of scopolaminetreated mice, as indicated by decreasing acetylcholinesterase (AChE) activity, elevating choline acetyltransferase (ChAT) activity and acetylcholine (Ach) level, increasing superoxide dismutase (SOD) activity and lowering the level of malondialdehyde (MDA) in the hippocampus of scopolamine-treated mice. Moreover, for the first time, Rh1 was found to significantly upregulate the expression levels of CREB, early growth response-1 (Egr-1), c-Fos and c-Jun in the hippocampus of scopolamine-treated mice. Conclusion: These results demonstrated that Ginsenoside Rh1 might exert a significant neuroprotective effect on cognitive dysfunctions induced by scopolamine, driven in part by the modulation of cholinergic activity, oxidative stress level and upregulation of CREB, Egr-1, c-Fos and c-Jun expression in the hippocampus.