The present study investigated the protective effect of mulberry vinegar (MV) on inflammatory responses and cognitive deficit induced by lipopolysaccharide (LPS) in mice models. The mice were administered MV and given intraperitoneal injection of LPS. In behavioral tests, MV ameliorated memory deficit and cognitive dysfunction. In the LPS-injected mouse brains, the generation of malondialdehyde, reactive oxygen species, nitric oxide, and pro-inflammatory cytokines was inhibited by the administration of MV. These preventive roles of MV were attributed to inactivation of NF-κB signaling pathway with downregulation of iNOS and COX-2. Moreover, MV modulated the amyloidogenic pathway by inhibiting amyloid precursor protein, beta-site APP cleaving enzyme-1, presenilin 1, and presenilin 2 and enhancing Aβ degradation-related proteins expression. The major phenolic compounds in MV were protocatechuic acid (0.13 mg/mL), rutin (0.13 mg/mL), and chlorogenic acid (0.05 mg/mL), which were increased by fermentation, confirmed by HPLC/UV analysis. Therefore, MV could ameliorate cognitive deficits through regulation of oxidative stress, inflammatory responses, and amyloidogenesis.