Inflammation is a common hallmark of neurodegenerative disorders. Systemic inflammation is usually associated with cognitive deficits. Scutellarin is a flavone with established antioxidant, anti-inflammatory, and neuroprotective effects. In this study, the effect of this flavone in prevention of lipopolysaccharide (LPS)-induced cognitive deficit was evaluated. LPS was i.p. injected at a dose of 500 μg/kg/day and scutellarin was administered i.p. at doses of 5, 25, or 50 mg/kg/day. Treatment of LPS-injected rats with scutellarin dose-dependently ameliorated deficits of spatial recognition memory in Y maze, discrimination index in novel object discrimination task, and retention and recall index in passive avoidance test. Additionally, scutellarin lowered hippocampal malondialdehyde (MDA) and potentiated antioxidant defense elements comprising superoxide dismutase (SOD), catalase, and glutathione (GSH) in addition to reduction of acetylcholinesterase (AChE) activity. Furthermore, scutellarin decreased hippocampal nuclear factor-kappaB (NF-κB), tumor necrosis factor α (TNFα), interleukin 6 (IL-6) and elevated nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Inappropriate alterations of authophagy markers including beclin-1, LC3 II, mTOR, and P62 were also prevented in the presence of scutellarin. Our findings demonstrate that scutellarin alleviates LPS-induced cognitive disturbances, however, the precise mechanism remains still speculative.