Iridoid glycosides (IG), the major active fraction of F. syringae leaves has been demonstrated to have strong anti-inflammatory properties to ulcerative colitis (UC) in our previous study. The aim of this study was to investigate whether IG modulates the inflammatory response in experimental colitis at the level of NF-κB signal pathway and epithelial cell apoptosis. UC in rats was induced by administration with dextran sulfate sodium (DSS) in drinking water. The inflammatory damage was assessed by disease activity index (DAI), macroscopic findings, histology and myeloperoxidase (MPO) activity. The effect of IG on pro-inflammatory cytokines TNF-α, IL-8, COX-2 and regulatory peptide TGF-β1 was measured. Epithelial cell apoptosis and the protein and mRNA expressions of Fas/FasL, Bcl-2/Bax, caspase-3, NF-κB p65, IκBα, p-IκBα and IKKβ were detected by TUNEL method, immunohistochemistry, Western blotting and real-time quantitative PCR, respectively. IG significantly ameliorated macroscopic damage and histological changes, reduced the activity of MPO, and strongly inhibited epithelial cell apoptosis. Moreover, IG markedly depressed TNF-α, IL-8, COX-2 and TGF-β1 levels in the colon tissues in a dose-dependent manner. Furthermore, IG significantly blocked of NF-κB signaling by inhibiting IκBα phosphorylation/degradation and IKKβ activity, down-regulated the protein and mRNA expressions of Fas/FasL, Bax and caspase-3, and activated Bcl-2 in intestinal epithelial cells. These results demonstrated for the first time that IG possessed marked protective effects on experimental colitis through inhibition of epithelial cell apoptosis and blockade of NF-κB signal pathway.