Stragaloside IV with immune regulation, organ protection, hypoglycemic, anti-inflammatory, antiviral, adjust the cell apoptosis and many pharmacological functions such as reproductive toxicity. We investigated for the first time whether the potential protective effect of stragaloside IV weakens cognitive deficits of septic-associated encephalopathy (SAE) in a mouse model. Moreover, the possible mechanisms of protection were also explored. Mice were received with a dose of 9 mg/kg stragaloside IV body weight for 20 weeks. Open Field Tests, Morris Water Maze Tests, Y Maze Tests and Serum Ammonia Assay were used to quantify the treatment with stragaloside IV on cognitive deficits in SAE rats. Microvessel density (MVD), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-PX), Nuclear transcription factor-kappa (NF-kappa B) p65 unit and Tumor necrosis factor alpha (TNF-alpha) were analyzed by ELISA kits. The inducible nitric oxide synthase (iNOS) protein expression was measured using western blotting analysis. Administration of stragaloside IV significantly weakens cognitive deficits, reduced the MDA, CAT, SOD, GSH-PX, NF-kappa B p65 unit and TNF-alpha levels, suppressed the iNOS protein expression in SAE rat. Our study indicated that stragaloside IV could prevent cognitive deficits of SAE rat through anti-oxidative and anti-inflammation.