Aged adults are prone to both short- and long-term complications following sepsis due to ineffective therapy. Phosphatidylserine (PS) is a membrane nutrient supplement known to enhance cognition and brain function, but its potential effects in treating sepsis are not well-documented. Our study aimed to explore the potential of PS in improving outcomes in sepsis and sepsis-associated encephalopathy (SAE). Middle-aged mice were administered PS for two months following induction of sepsis by lipopolysaccharides. The results indicated a significant increase in the survival rate of mice treated with PS after sepsis. Surviving mice underwent open field and shuttle box tests 45 days post-sepsis, revealing potential alleviation of neurobehavioral impairments due to PS pretreatment. Analysis at 60 days post-sepsis euthanasia showed reduced cleaved-caspase 3 in neurons and glial cell markers in the PS-treated group compared to the untreated sepsis group. Furthermore, PS administration effectively reduced proinflammatory cytokine gene expression in the hippocampus of mice with SAE, potentially inhibiting the TBK1/NLRP3/ASC signaling pathway. In the gut, PS pretreatment modulated β-diversity while maintaining jejunal morphology and colon ZO-1 expression, without significantly affecting α-diversity indices. Our findings suggest that PS administration improves survival rates, modulates the gut microbiome, preserves gut integrity, and ameliorates brain pathology in survived mice after sepsis. Importantly, these findings have significant implications for sepsis treatment and cognitive function preservation in aging individuals, providing new insights and sparking further interest and investigation into the potential of PS in sepsis treatment.Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.