Fermentation of dietary fiber and metabolism of polyphenols by the gut microbiota produce short chain fatty acids (SCFAs) and some simple phenolic acids, both of which have been independently shown to have anti-inflammatory effects and to improve gut health. While synergistic interactions between the two colonic metabolite groups have been speculated, direct evidence on whether and how these compounds work together towards collective anti-inflammatory effect and gut health remain unclear. In this study, the most important SCFA butyric acid (BtA) and three phenolic metabolites benzoic acid (BzA), phenylacetic acid (PAA) and phenylpropionic acid (PPA) were selected and assessed for the anti-inflammatory effects and the underlying mechanisms in a TNF-α-induced Caco-2 cell model. Significantly stronger inhibition of TNF-α-induced IL-8 production was found in cells pre-treated with different concentrations of mixtures of BtA and the phenolic metabolites than individual compounds. Further study showed that the synergistic effect was via significant down-regulation of the gene expressions of IL-8, TNF-α and VCAM-1, and of phosphorylation of JNK, p38 and IĸBα, cellular signaling mediators of the MAPK and NF-κB pathways. Although these are results of a cell model, they do provide significant insights into the synergistic anti-inflammatory effects between SCFAs and phenolic metabolites. As both metabolite groups are simultaneously present in the gut, our findings therefore also suggest a potential synergistic effect between the two colonic metabolite groups in maintaining gut health.