Technical Abstract: Age-related increases in oxidative stress and inflammation are associated with loss of cognitive and motor functions. Previous research has shown that supplementation with berry fruits can modulate signaling in primary hippocampal neurons or BV-2 mouse microglial cells. Because of the high polyphenolic content, we explored the protective effect of acai berry (Euterpe oleracea Mart) on BV-2 mouse microglial cells. Freeze-dried fractions of acai berry extracted with different polar solvents were applied to BV-2 cells to assess possible cytotoxicity. Except for the ethyl acetate fraction, all the other fractions had no significant cytotoxic effect. The study investigated whether mitigation of oxidative stress and inflammation by acai extracts is due to decreases in nitrite production, inducible nitrous oxide synthase (iNOS) expression and modification of other defensive signals. All fractions significantly reduced the nitrite production induced by lipopolysaccharide (100ng/ml), which was correlated with a significant concentration-dependent decrease in iNOS expression. The protection of microglial cells by acai berry extracts was also accompanied by the significant concentration-dependent reduction in pro-inflammatory mediators such as cyclooxygenase-2, p38 mitogen-activated protein kinase, and transcription factors such as tumor necrosis factor-alpha and nuclear factor kappa-b. The current study offers valuable insights into the protective effects of acai berry extracts on brain cells, which could have implications for improved cognitive and motor functions.