Abstract Background Escin is a triterpenoid saponin extracted from the dried mature seeds of Aesculus wilsonii Rehd. (Hippocastanaceae). This study aimed to investigate the effects of Escin on dextrose sodium sulfate (DSS)-induced mice. Methods Our investigation included in vivo assessments of Escin’s therapeutic potential against DSS-induced colitis through efficacy and safety evaluation. Potential targets of Escin were identified using a network pharmacology approach combined with molecular docking. Additionally, flow cytometric analysis was performed to evaluate immune cell subsets and macrophage polarization within spleen and colon tissues. In vitro experiments utilized lipopolysaccharide (LPS)-stimulated RAW264.7 cells and bone marrow-derived macrophages (BMDM) to elucidate relevant mechanisms. Results Escin demonstrated significant therapeutic potential against DSS-induced colitis by ameliorating disease symptoms, restoring intestinal barrier integrity, and reducing proinflammatory cytokine production in colonic tissues. Furthermore, it demonstrated favorable hepatorenal safety profiles. Network pharmacology analysis identified the NF-κB signaling pathway as a central target, and molecular docking further revealed strong binding affinities between Escin and key proteins involved in NF-κB signaling, such as IKBKB and TNF. Flow cytometry revealed that Escin exerted immunomodulatory effects in vivo by suppressing pro-inflammatory M1 macrophages while promoting anti-inflammatory M2 macrophages within colon tissues. In vitro, Escin inhibited blockade of NF-κB activation in both LPS-stimulated BMDM and RAW264.7 cells, and Escin exhibited robust anti-inflammatory activity in LPS-stimulated BMDM by remodeling macrophage polarization. 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