Chicoric acid (CA), a natural phenolic acid extracted from chicory and the echinacea (purple coneflower) plant (Echinacea purpurea), has been regarded as a nutraceutical that has powerful antioxidant and antiobesity activities. We investigated the inhibitory effects of CA on systemic inflammation‐induced neuroinflammation, amyloidogenesis, and cognitive impairment. C57BL/6J mice were treated with 0.05% CA in the drinking water for 45 d. The mice were then treated by intraperitoneal injection of lipopolysaccharide (LPS). It was found that CA prevented LPS‐induced memory impairment and neuronal loss through behavioral tests and histological exam‐ination. Furthermore, amyloidogenesis in the CNS was detected. The results showed that CA prevented LPS‐induced increases in amyloid β (1–42 specific) (Aβ_1–42) accumulation, levels of amyloid precursor protein, and neuronal β‐secretase 1 (BACE1), as well as the equilibrium cholinergic system in mouse brain. Moreover, CA down‐regulated LPS‐induced glial overactivation by inhibiting the MAPK and NF‐κB pathway. Consequently, CA reduced the levels of NF‐κB transcriptionally regulated inflammatory mediators and cytokines such as iNOS, cyclooxygenase‐2 (COX‐2), IL‐1β, and TNF‐α in both mouse brain and BV2 microglial cells. These results demonstrated that CA alleviated memory impairment and amyloidogenesis triggered by LPS through suppressing NF‐κB transcriptional pathway, suggesting that CA might be a plausible therapeutic intervention for neuroinflammation‐related diseases such as Alzheimer disease. —Liu, Q., Chen, Y., Shen, C., Xiao, Y., Wang, Y., Liu, Z., Liu, X. Chicoric acid supplementation prevents systemic inflammation‐induced memory impairment and amyloidogenesis via inhibition of NF‐κB. FASEB J. 31, 1494–1507 (2017) www.fasebj.org