Bunchosia armeniaca (Cav.) DC (Malpighiaceae) is one of the well-known traditionally used remedies worldwide. This study aims to explore the leaves’ metabolome via Quadrupole-Time-of-Flight-Liquid-Chromatography-Mass Spectrometry and to investigate the neuroprotective effect of leaves using lipopolysaccharide (LPS) induced Alzheimer’s disease model. Mice were administered LPS (0.25 mg/kg/day; intraperitoneal) as well as methanolic extract (BME), dichloromethane (BDMF), and butanol (BBF) fractions (each 200 mg/kg/day; oral) for one week. BME and BBF improved behavioral activity on the Y maze test, decreased brain content of inflammatory markers such as nuclear factor kappa B and interleukin 1 beta, and prevented the elevation of cytochrome P450 2E1, and glial fibrillary acidic protein compared to the LPS-administered group. Histopathological examination of several brain parts confirmed the neuroprotective effect of the tested extracts. In addition, BBF exhibited higher activity in all tested in vitro antioxidant and acetylcholinesterase inhibition assays. Metabolic profiling offered tentative identification of 88 metabolites, including mainly flavonoids, phenolic acids, and coumarins. Several detected metabolites, such as quercetin, apigenin, baicalin, vitexin, and resveratrol, had previously known neuroprotective effects. The current study highlighted the possible novel potential of B. armeniaca in preventing memory impairment, possibly through its antioxidant effect and inhibition of acetylcholinesterase, inflammatory and oxidative stress mediators.