Rhein demonstrates therapeutic advantages in ulcerative colitis treatment through multi-target synergy and multi-pathways, yet its clinical application is limited by poor oral bioavailability due to low solubility and poor medication compliance caused by gastrointestinal irritation. The study constructed a composite oral colon-specific delivery system based on rhein-loaded Pickering emulsions (Rhein@Rh-CS/TPP PEs), in which rhein-chitosan conjugated nanoparticles (Rh-CS/TPP NPs) serving as emulsifier, aiming to enhance rhein' bioavailability, improve its anti-ulcerative colitis efficacy, and reduce side effects. Briefly, rhein was covalently modified onto chitosan to increase hydrophobicity of chitosan, then the synthesized Rh-CS/TPP NPs were served as solid particle emulsifier. The resulting Rhein@Rh-CS/TPP PEs were verified as an oral delivery system with pH-responsive, enzyme-triggered, and bioadhesive properties for colon-specific and sustained release. Rhein exerted synergistic anti-ulcerative colitis effects by inhibiting TLR4/NF-κB/MLCK pathway activation and up-regulating tight junction proteins ZO-1, claudin-3 and occludin. Additionally, the Pickering emulsions significantly improved rhein' bioavailability while mitigating intestinal irritation-induced nutrient loss. The work provides a new strategy for the safe and effective application of insoluble intestinal stimulant drugs in the treatment of ulcerative colitis.