ObjectiveTo explore the potential mechanism of acupuncture with the method of soothing the liver and regulating the mind in improving depressive disorder. MethodsEighteen C57BL/6J mice were randomly divided into blank group， model group， and acupuncture group， with 6 mice in each group. The model group and the acupuncture group were subjected to depression induction by intraperitoneal injection of lipopolysaccharide （LPS）， while the blank group received an equal volume of normal saline once daily for seven consecutive days. Concurrently， the acupuncture group received "soothing the liver and regulating the mind" acupuncture intervention starting from the first day of modeling， once daily for 14 days； whereas the blank group and the model group were only restrained without acupuncture. The sucrose preference test was used to assess sucrose preference rate， the open-field test to measure center stay time and total travel distance， and the forced swim test to evaluate immobility time. Hematoxylin-eosin （HE） staining was performed to observe hippocampal morphological changes. Enzyme-linked immunosorbent assay （ELISA） was used to detect levels of interleukin-1β （IL-1β）， interleukin-6 （IL-6）， and tumor necrosis factor-α （TNF-α） in hippocampal tissue. Western blot analysis was conducted to examine the protein expression levels of Toll-like receptor 4 （TLR4） and nuclear factor-κB （NF-κB） in the hippocampus. ResultsCompared to the blank group， the model group showed a significant reduction in sucrose preference rate， center stay time， and total travel distance， along with a significant increase in immobility time in the forced swim test， hippocampal IL-1β， IL-6， and TNF-α levels， as well as TLR4 and NF-κB protein expression （P＜0.01）， and the histological examination revealed blurred hippocampal neuronal boundaries， loose arrangement， and some neurons exhibiting nuclear pyknosis and deep staining. Compared to the model group， the acupuncture group demonstrated a significant increase in sucrose preference rate， center stay time， and total travel distance， along with a significant reduction in immobility time in the forced swim test， hippocampal IL-1β， IL-6， and TNF-α levels， and TLR4 and NF-κB protein expression （P＜0.01）， and the histological analysis showed that hippocampal neurons in the acupuncture group were more tightly arranged， with reduced nuclear pyknosis and deep staining. ConclusionAcupuncture with the "soothing the liver and regulating the mind" method can significantly improve depression-like behavior， potentially by inhibiting the hippocampal TLR4/NF-κB signaling pathway and alleviating inflammatory responses.