Ulcerative colitis (UC) remains an intractable and relapsing disease featured by intestinal inflammation. The anti-UC activity of Akkermansia muciniphila (AKK), an intestinal microorganism, has been widely investigated. The current work is to explore the impacts of AKK on UC and its possible reaction mechanism. In vivo UC model was induced by dextran sulfate sodium (DSS) and phorbol-12-myristate-13-acetate (PMA)-induced THP-1-M0 and raw264.7 macrophages were treated by lipopolysaccharide (LPS). H&E staining evaluated tissue damage. Inflammatory and oxidative stress levels were assessed by relevant kits. The high-throughput analysis of fatty acids was performed by the LC/MS method. RT-qPCR and Western blot detected related gene expression. Flow cytometry measured cell apoptosis and macrophage polarization. Energy metabolism was detected by ELISA, related assay kits, JC-1 staining, and Western blot. AKK reduced the pathological damage of mice colon tissues, alleviated oxidative stress and inflammatory response, upregulated the expression of Occludin-1 and SCFAs receptors, and stimulated M1 to M2 macrophage polarization in vivo. After FFAR2 was silenced, the promoting role of AKK in the viability and M1 to M2 macrophage polarization and the inhibitory role in oxidative stress, inflammation, apoptosis, energy metabolism disorder, necroptosis, and pyroptosis were both reverted. Conclusively, AKK might mediate SCFAs-SLC52A2/FFAR2 pathways to exert protective activities against intestinal inflammatory response in UC, suggesting that AKK might represent a novel and promising candidate for UC therapy.