Background Neuroinflammation and oxidative stress are two major pathological characteristics of Alzheimer's disease (AD). Amyloid-beta oligomers (A beta O), a toxic form of A beta, promote the neuroinflammation and oxidative stress in the development of AD. Isoliquiritigenin (ISL), a natural flavonoid isolated from the root of liquorice, has been shown to exert inhibitory effects on inflammatory response and oxidative stress. Objectives The main purpose of this study is to assess the influence of ISL on inflammatory response and oxidative stress in BV2 cells stimulated with A beta O, and to explore the underlying molecular mechanisms. Methods 3-(4,5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H- tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) cytotoxicity assays were used to assess the toxic or protective effects of ISL. The expression levels of interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assays. Morphological changes in BV2 cells were assessed by immunofluorescence method. Nitric oxide (NO) assay kit was used to determinate the NO production. Western blot, qRT-PCR and immunofluorescence were used to explore the underlying molecular mechanisms. Results ISL treatment reduced the production of inflammatory cytokines and NO, and alleviated the morphological changes in BV2 cells induced by A beta O. ISL treatment further protected N2a cells from the toxic medium of A beta O-stimulated BV2 cells. ISL activated nuclear factor erythroid-2 related factor 2 (Nrf2) signaling and suppressed nuclear factor-kappa B (NF-kappa B) signaling in BV2 cells. Conclusion ISL suppresses A beta O-induced inflammation and oxidative stress in BV2 cells via the regulation of Nrf2/NF-kappa B signaling. Therefore, ISL indirectly protects neurons from the damage of toxic conditioned media.