Alzheimer’s disease (AD) is a neurological disease that leads to cognitive deficits in aged people. There are numerous pathological hallmarks, among them the classical hallmark is β-Amyloid (Aβ), which induces inflammatory events and phagocytic ability of phagocytic cells (such as microglial cells). Until now, the role of atraric acid (AA) in the prevention of AD has not been reported. The study was designed to investigate the contribution of AA to Aβ-induced microglial activation and cognitive deficits. The Aβ-induced AD model was crossed with the AA-treated mice, followed by cognitive and pathological tests. These effects were assessed via western blot, confocal microscopy, Thioflavin-S, Nissl staining, and with behavioral tests (MWM & YM). The cognitive deficit was assessed via the Morris water Maze (MWM) and Y-maze (YM). The Aβ deposition and microglial recruitment were observed by Thioflavin-S and immunohistochemistry. The neuroinflammatory and oxidative stress signaling were identified by western blotting and immunological assays (ROS & LPO), respectively, in brain hippocampal homogenates. Neuronal loss and survival were examined by Nissl staining. The mice treated only with Aβ1−42 i.c.v. shows cognitive and memory deficits, leading to a neurodegenerative condition in mice. In contrast, the intraperitoneal (i.p) delivery of AA (20 mg/kg, for 4 weeks) after the Aβ1−42 injection reduced the amyloid beta (Aβ) burden and glial cells overactivation via inhibiting their surface receptors. Similarly, the AA reduced the oxidative stress by reducing the level of ROS and LPO in brain hippocampal homogenates, as well as enhanced the level of natural endogenous antioxidant proteins and enzymes (Nrf-2 and HO-1) in the Aβ1−42 + AA co-treated group. Moreover, AA retained the neuronal integrity and morphology in the mouse hippocampal brain region, which demonstrates that AA could potentially serve as an anti-inflammatory, antioxidant in progressive neurodegenerative diseases (i.e., AD). Keywords: Amyloid-βeta (Aβ1−42) · Neuroinflammation · Oxidative stress · synaptic dysfunction · Alzheimer disease (AD) · Atraric Acid (AA).