ScopeInflammation is the pathological basis of many chronic diseases, and persistent intestinal inflammation is a key factor in the further development of colon cancer. Egg‐derived peptides have been proven to have anti‐intestinal inflammation activity. Egg white treated with salt contains a lot of rich protein, whether its peptides have anti‐inflammatory activity and how their mechanism of action is still unclear.Methods and ResultsIn this study, ELISA is used to determine the anti‐inflammatory activity of the peptides (VF‐4 and DR‐8 from salted egg white), and then RNA‐seq is used to explore the mechanism of their anti‐inflammatory activity, and then verified by western blotting and inhibitors. The results show that VF‐4 and DR‐8 significantly inhibit TNF‐α‐induced IL‐8 secretion in HT‐29 cells in a concentration‐dependent manner, and VF‐4 show a more significant anti‐inflammatory effect than DR‐8. The anti‐inflammatory mechanism of VF‐4 and DR‐8 is through inhibiting the activation of Nuclear factor kappa B (NF‐κB), mitogen‐activated protein kinase (MAPK), and phosphatidylinositol 3' ‐kinase(PI3K)‐Akt pathways, reducing the production of inflammatory mediators.ConclusionVF‐4 and DR‐8 have obvious anti‐inflammatory activity, which can reduce intestinal inflammation and inhibit its further development into colon cancer.