This study aims to investigate the antidepressant mechanism of Acorus tatarinowii volatile oil by using network pharmacology and experimental validation.Firstly,TCMSP,CNKI,PubChem and SwissTarget Prediction databases were used to obtain the chemical composition and targets of the A. tatarinowii volatile oil.DisGeNET,DrugBank,GenCards,OMIM,and TTD databases were used to obtain the disease targets of depression.Then the relationship between the potential active ingredients,core targets and action pathways of the A. tatarinowii volatile oil in treating depression were analyzed using Venn,Cytoscape 3.10.1,Sring and DAVID databases.And finally,the experimental results were validated by establishing the lipopolysaccharide-induced depressive-like mouse model.The results of network pharmacology showed that the active ingredients of A. tatarinowii volatile oil for treating depression may be alloaromadendrene,α-pinene,β-asarone and other five ingredients,and the key targets may be prostaglandin-endoperoxide synthase 2 (PTGS2),interleukin-1β (IL-1β),interleukin-6 (IL-6),and tumor necrosis factor-α (TNF-α),which mainly enriched in nuclear factor kappa B (NF-κB),interleukin-17 (IL-17),tumor necrosis factor (TNF) and other signaling pathways.The in vivo experimental results showed that the A. tatarinowii volatile oil significantly reduced depressive-like behaviors in mouse,improved their physiological state,and reduced the mRNA expression levels of PTGS2,IL-1β,IL-6,and TNF-α in the hippocampus of depressed mouse (P<0.01),and decreased the number of PTGS2 and ionized calcium-binding adaptor molecule-1 (Iba1) positive cells in the hippocampus.The study suggested that the A. tatarinowii volatile oil can effectively improve depression,and the mechanism of action may be related to the inhibition of NF-κB,IL-17 and TNF signaling pathways.