Objective To observe the effect of gypenosides (GYPs) on brain injury in septic rats and explore its mechanisms. Methods Sprague-Dawley rats were divided into the sham, sepsis-associated encephalopathy ( SAE), GYPs, GNE-317, and GYPs + GNE-317 groups. The SAE model was constructed via cecal ligation and perforation. Two hours after establishing the model, the rats were administered normal saline, normal saline, 200 mg / kg GYPs solution, 40 mg / kg GNE-317 solution or 200 mg / kg GYPs + 40 mg / kg GNE-317 solution, respectively, by irrigation at 2 mL/ d, continually administered for 3 days. The reflex test was used to evaluate the rats’ neural behavior, then the rats were killed and their hippocampuses were removed, hematoxylin and eosin staining was used to observe the pathological damage to the hippocampus, TUNEL testing was used to detect apoptosis in the hippocampus, MDA levels and SOD activity were detected using kits, and the expressions of phosphatidylinositol-3-kinase ( PI3K), protein kinase B ( Akt), p-Akt, apoptosis regulator Bax, Bad and caspase-3 proteins were detected via Western blot. Results Rats in the sham group were in good condition, and the morphology and structure of the hippocampal neurons were normal. Rats in the SAE group exhibited somnolence, lack of spontaneous activity, and diffuse neuronal damage. Rats in the GYPs group exhibited normal activity and neuronal morphology. Rats in the GNE-317 group exhibited worse activity and neuronal morphology than that of the SAE group. Rats in the GYPs + GNE-317 group showed similar symptoms to those of the SAE group. Compared with those of the sham group, the proportion of apoptotic cells, the MDA levels, and the expressions of cleaved-caspase-3, Bax and Bad were higher in the SAE group (P< 0. 05), whereas these indexes were lower in the GYPs group than in the SAE group (P< 0. 05), higher in the GYPs + GNE-317 group than in the GYPs group, and lower in the GYPs + GNE-317 group than in the GNE-317 group (P< 0. 05). Compared with those of the sham group, the neurobehavioral score, SOD activity, PI3K and p-Akt levels were lower in the SAE group (P< 0. 05) and higher in the GYPs group than in the SAE group (P< 0. 05). These indexes were lower in the GYPs + GNE-317 group than in the GYPs group and higher than those in the GNE- 317 group (P< 0. 05). Conclusions GYPs promoted activation of the PI3K/ Akt pathway in the hippocampus, inhibited the release of downstream apoptogenic factors, reduced oxidative stress, and alleviated brain injury in SAE-induced rats.