Inflammatory bowel disease (IBD) is a multifactorial chronic inflammation of the intestine and has become a global public health concern. A farnesoid X receptor (FXR) was recently reported to play a key role in hepatic-intestinal circulation, intestinal metabolism, immunity, and microbial regulation, and thus, it becomes a promising therapeutic target for IBD. In this study, we identified a series of nonbile acid FXR agonists, in which 33 novel compounds were designed and synthesized by the structure-based drug design strategy from our previously identified hit compound. Compound 33 exhibited a potent FXR agonistic activity, high intestinal distribution, good anti-inflammatory activity, and the ability to repair the colon epithelium in a DSS-induced acute enteritis model. Based on the results of RNA-seq analysis, we further investigated the therapeutic potential of the combination of compound 33 with 5-ASA. Overall, the results indicated that compound 33 is a promising drug candidate for IBD treatment.