BackgroundUlcerative colitis (UC) is a common type of inflammatory bowel disease. Due to the elusive pathogenesis, safe and effective treatment strategies are still lacking.Fraxini Cortex(FC) has been widely used as a medicinal herb to treat some diseases. However, the pharmacological mechanisms of FC for UC treatment are still unclear.MethodsAn integrated platform combining network pharmacology and experimental studies was introduced to decipher the mechanism of FC against UC. The active compounds, therapeutic targets, and the molecular mechanism of action were acquired by network pharmacology, and the interaction between the compounds and target proteins were verified by molecular docking. Dextran sulfate sodium (DSS)-induced colitis model was employed to assess the therapeutic effect of FC on UC, and validate the molecular mechanisms of action predicted by network pharmacology.ResultsA total of 20 bioactive compounds were retrieved, and 115 targets were predicted by using the online databases. Ursolic acid, fraxetin, beta-sitosterol, and esculetin were identified as the main active compounds of FC against UC. PPI network analysis identified 28 FC-UC hub genes that were mainly enriched in the IL-17 signaling pathway, the TNF signaling pathway, and pathways in cancer. Molecular docking confirmed that the active compounds had high binding affinities to the predicted target proteins. GEO dataset analysis showed that these target genes were highly expressed in the UC clinical samples compared with that in the healthy controls. Experimental studies showed that FC alleviated DSS-induced colitis symptoms, reduced inflammatory cytokines release, and suppressed the expression levels of IL1β, COX2, MMP3, IL-17 and RORγt in colon tissues.ConclusionFC exhibits anti-UC properties through regulating multi-targets and multi-pathways with multi-components.In vivoresults demonstrated that FC alleviated DSS-induced colitis.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12906-023-03983-0.