The intention behind the present work was to develop a microsphere based novel dosage form for sustained delivery of Omeprazole. Omeprazole is a proton pump inhibitor that suppresses gastric acid secretion by specific inhibition of the H+/K+-ATPase in the gastric parietal cell. By acting specifically on the proton pump, omeprazole blocks the final step in acid production, thus reducing gastric acidity. The microsphere system is based upon the fact that their structure can entrap the drug within them. Comparative study of the Emulsion solvent evaporation method and spray drying technique was done for the preparation of Microspheres using Eudragit RS 100 and Ethyl cellulose with various drug-polymer ratios. For optimization purpose, several factors which affect microsphere’s physical properties were investigated. A 32 full factorial design was employed to systematically optimize the drug release profile, encapsulation efficiency & drug content. Characterization techniques followed for the formed microspheres were FTIR, SEM, XRD and Particle size analysis along with the drug content, production yield, encapsulation efficiency and in vitro drug release. The in vitro dissolution studies were done to assess the release pattern of the drug from the Microspheres over a twelve hour period. Microspheres were able to sustain the release of omeprazole upto 12 hrs. All the formulations followed Hixon Crowell & Korsemayer Peppas model kinetics. From the FTIR study it is found that by both the methods Process parameters does not make any structural changes in Omeprazole. XRD study showed that sharp peaks for the pure drug & formulation by both the methods were obtained at the same diffraction angle. Hence, known to possess same internal structure. The mean particle size of Microspheres prepared by both the methods was found in the range of 1-1000 nm. The SEM study was done to evaluate Morphology and surface topography of prepared microspheres. The stability study conducted for optimized formulations of both the methods revealed that formulation is stable having no impact on physical appearance & drug release. In this Study sustained release Microspheres of Omeprazole were prepared successfully by Spray Drying method and Emulsion Solvent Evaporation Method and comparison between the two has been done.