In this study, oral colon-targeted adhesion core-shell nanoparticles were designed by applying FA-Zein as the core and using pectin as the shell to enhance the low bioavailability exhibited by glycyrrhizic acid (GA) and the anti-inflammatory effect in specific parts of the intestine. As indicated by the results, the nanoparticles (NPs) remained stable in the stomach and small intestine, while pectins began to degrade and release GA in considerable amounts in the colon with the abundant flora. Subsequently, folate-acid targeting was further assessed with Raw 264.7 and NCM 460 cells. Lastly, NPs were reported to exhibit high adhesion on the colon by using the DSS-induced ulcerative colitis mouse model. Moreover, as indicated by in vitro and in vivo studies, nanoparticles could decrease the levels of MPO and TNF-α by reducing macrophages and neutrophils. In brief, this study provides an ideal loaded natural anti-inflammatory drug delivery system to treat ulcerative colitis.