This study aims to investigate the therapeutic mechanism of Portulacae Herba extract (PHE) on sepsis-induced liver injury (SILI) based on network pharmacology and experimental verification. The chemical components of PHE were analyzed by ultra-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS). Network pharmacology was used to screen the key components and targets of PHE for therapeutic effects. Molecular docking and molecular dynamics simulation were conducted to further clarify the stability of the binding between key components and targets at the molecular level. Subsequently, normal group, SILI group, PHE high-dose, medium-dose, and low-dose groups, and dexamethasone group were established. The therapeutic effect and mechanism of PHE were verified by detecting the pathological damage of rat liver, liver function indicators, expression of inflammatory factors, and expression of related pathway proteins. UPLC-Q-TOF-MS/MS analysis identified 34 compounds, and network pharmacology analysis obtained 5 core targets including tumor necrosis factor (TNF), interleukin-6 (IL-6), serine/threonine kinase 1 (AKT1), IL-1β and albumin (ALB), as well as five main chemical components including quercetin, luteolin, kaempferol, arachidonic acid, and β-sitosterol. The related pathways were enriched in the phosphoinositide 3-kinase (PI3K)-AKT and mitogen-activated protein kinase (MAPK) pathways. The animal experiment results showed that compared with the SILI group, the PHE medium-dose and low-dose groups could effectively alleviate the pathological damage and liver function indicators of SILI(P<0. 05), and the high-dose group had the most significant effect (P<0. 001). The medium-dose and low-dose PHE groups also significantly reduced the expression of inflammatory factors in liver tissue (P<0. 05), and the high-dose group had the most significant effect (P<0. 001). At the same time, PHE inhibited the phosphorylation of p38 MAPK, PI3K, and AKT. This study revealed that PHE has a therapeutic effect on SILI, which may be achieved through multiple targets and inhibition of the phosphorylation of the PI3K/AKT and MAPK pathways.