As the incidence of ulcerative colitis (UC) has increased globally, there is a great unmet clinical need for efficacious, tolerable, and economical, orally administered drugs for its treatment. To help meet this need, we investigated anti-inflammatory small-molecule drugs with a novel structure, high activity, and high selectivity for the treatment of UC. Here, we designed and synthesized a series of novel anti-inflammatory compounds based on the molecular hybridization strategy by merging fragments from anti-inflammatory drugs. Among them, compound 11a best-exhibited lipopolysaccharide (LPS)-induced inflammation in RAW264.7 cells in vitro. Anti-inflammatory mechanism studies showed that compound 11a inhibited the release of pro-inflammatory cytokines and alleviated the inflammatory process by blocking the activation of the ASK1/p38 MAPKs/NF-kappaB signaling pathway in LPS-stimulated RAW264.7 cells. Analysis of the in vivo biological activity showed that compound 11a significantly alleviated dextran sodium sulfate-induced ulcerative colitis in mice while demonstrating an excellent safety in acute toxicity tests. Our study provides a novel compound for the treatment of UC that is worthy of further investigation and structural optimization.