Theabrownins (TB), a signature phenolic-derivative via complex microbial fermentation, has multiple health-promoting effects, including antioxidant, anti-obesity and hypoglycemic effects. However, the effect of TB on colitis remains unclear. In this study, we investigated the effect of TB on DSS-induced colitis in mice. TB treatment significantly relieved weight loss (p < 0.001), retained a longer colon length (p < 0.01), ameliorated severe crypt damage. Furthermore, TB downregulated the protein of inflammatory cytokines (IL-1β, IL-6 and TNF-α (p < 0.01)) in colitis mice. In addition, TB administration could suppress macrophage aggregation into colon by reducing expression levels of CD 68 + and CD 11b. TB effectively prevented DSS-induced colitis might be attributed to up-regulation of PPAR-γ expression and down-regulation of p-NF-κB expression on the protein level. Overall, this study suggested that TB attenuated inflammation and colitis progression via modulating PPAR-γ and NF-κB signaling pathways, indicating its potential as a functional food for anti-inflammatory.