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There is a strong linkage between Insomnia and Alzheimer’s disease (AD). Statistical data revels that sleep disturbances and dementia increases with advancing age and young and middle-aged adults who suffer from insomnia are 11 times more likely to develop AD and depression in their later life. The present study is designed to evaluate anti amnesic activity of methanolic extract of Nardostacys jatamansi DC (MENJ) rhizome on sleep deprived (SD) amnesic mice. Animals were pretreated with MENJ for 14 days (200 and 400 mg/kg, orally) and Piracetam (200 mg/kg, orally) followed by 5 days sleep deprivation using multiple platform method. The Acetylcholinesterase (AChE) activity, glutamate, antioxidants enzymes Superoxide dismutase (SOD), Catalase (CAT), Glutathione reductase (GRD), Glutathione peroxidase (GPx), Lipid peroxidase assay (LPO) and ascorbic acid (Vit. C) are estimated from mice brain on 19th day. MENJ at doses of 200 mg/kg and 400mg/kg treated groups showed a significant inhibition of AChE activity and improved antioxidants enzyme levels in sleep deprived amnesic mice. These findings suggest MENJ exerts a protective effect against loss of memory and cognitive deficits due to its inhibition of AChE and protection from oxidative damage due to sleep deprivation.