The aim of this present research work was to prepare and evaluate alginate microspheres of aceclofenac by ionic gelation method for targeting the drug release in intestinal region and decrease distinct tissue protection in the stomach. This method offers to prepare microspheres which are important in controlling the release rate and the absorption of aceclofenac from the intestinal region. Variation in polymer concentration was studied systemically for their influence on the encapsulation efficacy, particle size and in vitro drug release. The enteric nature of the microspheres showed very less amount of drug released in acidic medium. The mucoadhesion property was strongly dependent on the pH of the medium and the polymer concentration in the formulations. In vitro drug release study proposed a mixed drug release mechanism, partially involving the sphere matrix disintegration and drug diffusion of the microspheres. Holm-Sidak multiple comparison analysis suggested a significant difference in measured t50% values among all the microsphere formulations. In vivo studies revealed that the anti-inflammatory effect induced by the aceclofenac loaded alginate microspheres was significantly high and prolonged than that induced by the pure aceclofenac. So, this aceclofenac loaded alginate microspheres exhibited promising properties to improve the patient compliance by controlling and prolonging the systemic absorption of aceclofenac along with a distinct tissue protection in the stomach.