Currently, the neuroprotectant and memory-enhancing agent for menopausal women with metabolic syndrome is required. Based on the advantages of polyphenolics on numerous changes observed in menopause with metabolic syndrome and the encapsulation method, we hypothesized that microencapsulated mulberry fruit extract (MME) could protect brain damage and improve memory impairment in an animal model of menopause with metabolic syndrome. To test this hypothesis, MME at doses of 10, 50, and 250 mg/kg was given to female Wistar rats which were induced experimental menopause with metabolic syndrome by bilateral ovariectomy (OVX) and fed with high-carbohydrate high-fat (HCHF) diet for 8 weeks. Spatial memory together with neuron density, oxidative stress status, acetylcholinesterase, and phosphorylation of Erk in the hippocampus was assessed at the end of the study. It was found that MME decreased memory impairment, oxidative stress status, and AChE activity but increased neuron density and Erk phosphorylation in the hippocampus. Therefore, the neuroprotective and memory-enhancing effects of MME might partly involve the enhanced cholinergic function and Erk phosphorylation but decreased oxidative stress status in hippocampus. Therefore, MME is the potential novel neuroprotectant and memory-enhancing agent for menopause with metabolic syndrome. However, further research especially clinical trial is still necessary.