Oral colon-specific drug delivery is of great interest for ulcerative colitis (UC) therapy. Here, an emulsion-solvent evaporation method was used to fabricate microparticles (MPs) with pH-sensitive Eudragit S100 (ERS100) and poly(lactide-co-glycolide) (PLGA), and the MPs were loaded with curcumin (an efficient anti-inflammatory agent). The resultant spherical MPs had a desirable particle size ranging from 1.52 to 1.91�μm. Their loading efficiency could be regulated by changing the weight ratios of ERS100 and PLGA, with some MPs exhibiting loading efficiencies over 80%. It was observed that the fast release of curcumin from MPs in buffers (pH 1.2 and 6.8) could be significantly decreased by increasing the PLGA content. ERS100/PLGA MPs with a weight ratio of 1:2 (MPs-4) were able to maintain sustained release of curcumin, releasing ∼48% of the initial drug load at pH 7.2–7.4 during a 20�h-incubation. Most importantly, in vivo experiments revealed that orally administered MPs-4 had a superior therapeutic efficiency in alleviating colitis in a UC mouse model, compared to curcumin. Collectively, our one-step-fabricated curcumin-loaded MPs have the properties of pH-sensitivity, controlled drug release and colon targeting, and thus, may hold promise as a readily scalable drug carrier for the efficient clinical treatment of UC.