Background: Maclura pomifera a member of Moraceae family, is a tropical plant with ethnobotanical uses. Objectives: The present study aimed to evaluate bioactive compounds, antioxidants, and acetylcholinesterase (AChE) inhibitory activities of different extracts of Tunisia M. pomifera (Rafin.) Schneid fruit in vitro and in vivo. Methods: Organic extracts in different polarities (chloroform, ethyl acetate, and acetone) were extracted from different parts of the fruit of M. pomifera (exocarp, mesocarp, and pips). Phenolic content, antioxidant activity, and anti-AChE activity were determined. The anti-amnesic effects of ethyl acetate extract of the exocarp of M. pomifera were measured in galactose-induced memory deficit mice by the Y maze. The levels of biomarkers and AChE activity were determined in brain tissues. Results: The obtained results showed that the ethyl acetate extract of exocarp contains the highest content of flavonoids and polyphenols 22.3mg quercetin equivalents per g of dry weight and 718.6 mg gallic acid equivalents per g of dry weight. The evaluation of antioxidant activities highlighted that the ethyl acetate extract of exocarp was the most active element. The study of the AChE inhibitory power demonstrated that the ethyl acetate extract of the exocarp had the greatest inhibitory activity. The ethyl acetate extract from the exocarp ameliorated cognitive performance and reversed the oxidative damage as compared to galactose group. Conclusion: M. pomifera fruit is a good source of natural antioxidants, which might help prevent oxidative stress-related damage and memory impairment in such mental disorders as Alzheimer’s disease (AD).