Ulcerative colitis (UC) is an idiopathic inflammatory condition of colorectal regions. Existing therapies for UC face grave lacunae including off-target and other harmful side effects, extensive first-pass metabolism, rapid clearance, limited or poor drug absorption and various other limitations, resulting in lower bioavailability. These conditions demand advanced delivery strategies to inflammatory colonic conditions so that drugs can counter stomach acid, avail protective strategies at this pH and selectively deliver drugs to the colon. Therefore, this approach was undertaken to develop and characterize nanoparticles for the delivery of drugs glycyrrhizic acid as well as budesonide in UC. Biocompatible and biodegradable aminocellulose-conjugated polycaprolactone containing budesonide was covered onto gelatinous nanoparticles (NPs) loaded with GA. Nanoparticles were prepared by the solvent evaporation technique, which showed particle size of ∼230 nm, spherical shape, almost smooth morphological characters under transmission, scanning and atomic force microscopy. These NPs also improved disease activities like occult blood in the stool, length of the colon and fecal properties. The nanoparticle therapy appreciably decreased colonic mast cellular infiltration, significantly maintained mucin protection, ameliorated histological features of the colon. Furthermore, markers of inflammation such as iNOS, COX-2, IL1-β, TNF-α, NO, and MPO were also appreciably ameliorated with the therapy of dual drug-loaded nanoparticles. Overall, these results establish that dual drug-loaded core-shell NPs exhibit superior therapeutic properties over the free or naïve forms of GA and budesonide in acute colon inflammation and present advantages that may be assigned to their ability to significantly inhibit colon inflammatory conditions.