This study aimed to develop curcumin microsponges to combat colonic inflammation. Curcumin has traditionally been recognized for its anti-inflammatory properties. However, their therapeutic potential is hindered by factors, such as low bioavailability, poor solubility in water, and instability in acidic and neutral environments. Additionally, its limited absorption from the intestine, hepatic metabolism, and rapid elimination limits its effectiveness. To address these issues, this study aimed to improve the solubility of curcumin by creating inclusion complexes with cyclodextrin. These complexes can enhance the therapeutic efficacy, reduce the required dosage, and facilitate drug loading into microsponges. This study commenced with the creation of curcumin inclusion complexes with cyclodextrin, which were assessed for their drug content, solubility, in vitro release, and structural characteristics. Additionally, microsponges of cyclodextrin were developed using a pH-sensitive polymers (Eudragit L100and S 100) and a pore former (PVA), guided by experimental design (Design Expert version 13) to optimize drug loading and release. The resulting formulations were subjected to FTIR, SEM, and anti-inflammatory activity evaluations using an acetic acid-induced rat colitis model. The inclusion complexes at a 1:1.5 ratio exhibited desirable characteristics, and the optimized microsponges demonstrated a three-fold increase in the drug release rate compared to the pure drug. The anti-inflammatory effect observed in the colon, as evidenced by the recovery of normal morphology after oral administration of the microsponges, indicated the potential of the optimized formulation for targeted drug delivery. In conclusion, curcumin microsponges developed using the eudragit combination showed anti-inflammatory effects on colonic tissues.