Microglial over-activation plays a crucial roles during neuroinflammation. Aldose reductase (AR) is one of the enzymes that has been linked to inflammatory processes in several diseases. Therefore, inhibition of AR is considered as an important strategy to reduce inflammation. In the present study, Quercetin (Q) and monochloropivaloylquercetin (MCPQ) showed potent inhibition on AR expression and anti-neuroinflammatory effects in Amyloid beta (A beta) peptide (1-42) induced inflammatory process by inhibiting expression of inflammatory mediators from microglial cells. Furthermore, ablation of AR caused a significant reduction on COX2 expression in A beta-induced neuroinflammation. Q and MCPQ suppressed COX2 mRNA and protein expression, which further resulted in downstream inhibition of prostaglandin E-2 (PGE(2)) release in A beta-induced neuroinflammatory process. Additionally, All treatment resulted in activation of Mitogen Activated Protein Kinase (MAPK) and increased translocation of Nuclear Factor Kappa B (NF kappa B). Q and Sorbinil significantly reduced the activation of MAPK, at the same time Q, MCPQ and sorbinil decreased nuclear translocation of NF kappa B and diminished tumor necrosis factor (TNF)-alpha release in A beta-induced neuroinflammation. The results suggested that AR is a probable target for treatment of neuroinflammation as well as Q and MCPQ could be effective agents for treating or preventing inflammation-related neurodegenerative diseases by AR inhibition.