The main objective of the work is to prepare mefenamic acid loaded microspheres for sustained release using different polymers ethyl cellulose as synthetic polymer and sodium alginate as natural polymer and compare and selecting best suitable polymer among them. For preparing mefenamic acid microspheres ethyl cellulose used as synthetic polymer in solvent evaporation method and sodium alginate as natural polymer used in inotropic gelation technique. All formulations were prepared by varying the drug and polymer concentrations. The obtained microspheres were characterized for surface morphology, stability and evaluated for yield, drug content, entrapment efficiency and Invitro drug release. Comparative study was performed between the best formulations of Ethyl cellulose and sodium alginate polymers. zeta potential value, Drug content, Entrapment efficiency of the best formulation of Mefenamic acid microspheres using ethyl cellulose was found to be -78.2mv, 93.4%, 92.5%whereas for using sodium alginate it was found to be -65.1mv, 91.7%, 90.1%respectively. The drug release was found to be 90.4% till 12hrs following first order rate constant with fickian diffusion for the best formulation using ethyl cellulose whereas for using sodium alginate, the drug release was 92% till 11hrs. Ethyl cellulose was found to be the best polymer for preparing the mefenamic acid microspheres with good stability, drug content, entrapment efficiency and sustained drug release for 12hours.