Inflammatory bowel disease (IBD), a global disease threatening human health, is commonly accompanied by secondary liver damage (SLD) mediated by the gut-liver axis. Oxidative stress acts a critical role in the onset of IBD, during which excessive oxidation would destroy the tight junctions between intestinal cells, promote proinflammatory factors to penetrate, and thereby damage the intestinal mucosa. Ficus pandurata Hance (FPH) is widely used for daily health care in South China. Our previous study showed that FPH protected acute liver damage induced by alcohol. However, there is no study reporting FPH treating ulcerative colitis (UC). This study is designed to investigate whether FPH could inhibit UC and reveal its potential mechanism. The results showed that FPH significantly alleviated the UC disease symptoms including the body weight loss, disease activity index (DAI), stool consistency changing, rectal bleeding, and colon length loss of UC mice induced by dextran sulfate sodium (DSS) and reversed the influences of DSS on myeloperoxidase (MPO) and diamine oxidase activity (DAO). FPH suppressed UC via inhibiting the TLR4/MyD88/NF-κB pathway and strengthened the gut barrier of mice via increasing the expressions of ZO-1 and occludin and enhancing the colonic antioxidative stress property by increasing the levels of T-SOD and GSH-Px and the expressions of NRF2, HO-1, and NQO1 and reducing MDA level and Keap1, p22-phox, and NOX2 expressions. Furthermore, FPH significantly inhibited SLD related to colitis by reducing the abnormal levels of the liver index, ALT, AST, and cytokines including TNFα, LPS, LBP, sCD14, and IL-18 in the livers, as well as decreasing the protein expressions of NLRP3, TNFα, LBP, CD14, TLR4, MyD88, NF-κB, and p-NF-κB, suggesting that FPH alleviated UC-related SLD via suppressing inflammation mediated by inhibiting the TLR4/MyD88/NF-κB pathway. Our study firstly investigates the anticolitis pharmacological efficacy of FPH, suggesting that it can be enlarged to treat colitis and colitis-associated liver diseases in humans.Copyright © 2021 Weibo Dai et al.