Oral drug delivery has been considered as a promising strategy for ulcerative colitis (UC) therapy. Here, an emulsion solvent evaporation technique was employed to prepare non-porous curcumin (CUR)-loaded polymeric nanoparticles (NPs) and porous CUR-loaded polymeric NPs in the absence or presence of ammonium bicarbonate. The resultant CUR-loaded NPs (non-porous NPs and porous NPs) had a desirable mean particle size of around 260 nm with a narrow size distribution, a uniform pore size distribution, slightly negative-charged surface, high encapsulation efficiency and controlled drug release capacity. In vitro experiments indicated that Raw 264.7 macrophages exhibited time-dependent accumulation profiles of NPs during the initial 2 h of co-incubation. Furthermore, we found that porous NPs inhibited the secretion of the main pro-inflammatory cytokines (TNF-α, IL-6 and IL-12) and the production of reactive oxygen species much more efficiently than non-porous NPs. Most importantly, in vivo studies demonstrated that oral administered porous NPs had a superior therapeutic efficiency in alleviating UC compared with non-porous NPs. The results collectively suggest that porous polymeric NPs can be exploited as efficient oral drug carriers for UC treatment.