Abstract: Background and Objective: Alzheimer disease (AD) is reflected by progressive cognitive debility usually start with impairment in the capability to form new memories, but unavoidably disturbing all knowledgeable tasks. The present study was aimed at investigating the neuroprotective effect aqueous extract of Spinacia oleracea (AESO) in scopolamine induced cognitive decline mice. Materials and Methods: Memory impairment was produced by administration of Scopolamine (1.4 mg kg–1 i.p.) in albino mice. Nootropic activity in mice with the treatment of AESO (200−400 mg kg–1) and donepezil (5 mg kg–1) were administered to different groups of mice. Effect of extract on learning and memory of mice was evaluated using elevated rectangular maze, pole climbing and morris water maze test and also estimated the brain acetylcholinesterase (AChE) concentration and the percentage of inhibition of AChE. Results: AESO showed significantly improved in learning and memory of mice, as indicated by the decline in transfer latency using rectangular maze test, decrease in escape latency during training, retrieval using morris water maze, pole climbing test and neuroprotective activity through reduced brain AChE concentration and increased the percentage of inhibition of AChE activity in rat brain. Conclusion: Thus, aqueous extract of Spinacia oleracea showed memory enhancing and neuroprotective activity in mice probably by inhibiting brain AChE activity.