Background: Panax ginseng Meyer (P. ginseng) is a traditional natural/herbal medicine. The ameliorationon inflammatory bowel disease (IBD) activity rely mainly on its main active ingredients that are referredto as ginsenosides. However, the current literature on gut microbiota, gut microbiota-host co-metabolites,and systems pharmacology has no studies investigating the effects of ginsenoside on IBD. Methods: The present study was aimed to investigate the role of ginsenosides and the possible underlyingmechanisms in the treatment of IBD in an acetic acid-induced rat model by integrating metagenomics,metabolomics, and complex biological networks analysis. In the study ten ginsenosides in theginsenoside fraction (GS) were identified using Q-Orbitrap LC-MS. Results: The results demonstrated the improvement effect of GS on IBD and the regulation effect ofginsenosides on gut microbiota and its co-metabolites. It was revealed that 7 endogenous metabolites,including acetic acid, butyric acid, citric acid, tryptophan, histidine, alanine, and glutathione, could beutilized as significant biomarkers of GS in the treatment of IBD. Furthermore, the biological networkstudies revealed EGFR, STAT3, and AKT1, which belong mainly to the glycolysis and pentose phosphatepathways, as the potential targets for GS for intervening in IBD. Conclusion: These findings indicated that the combination of genomics, metabolomics, and biologicalnetwork analysis could assist in elucidating the possible mechanism underlying the role of ginsenosidesin alleviating inflammatory bowel disease and thereby reveal the pathological process of ginsenosides inIBD treatment through the regulation of the disordered hosteflora co-metabolism pathway.