One of the most feasible approaches for achieving a prolonged and predictable drug delivery profiles in the GIT is to control the gastric residence time (GRT) using gastroretentive dosage forms. The aim of the present study is to prepare the floating microspheres of ketoprofen to sustain the drug release for longer time to overcome the short half life of the drug. The microspheres were prepared by emulsification-solvent evaporation technique using ethyl cellulose and heat denaturation technique using egg albumin as a natural polymer. The optimization of microspheres was carried out based on pentagonal design using response surface methodology. The floating microspheres were evaluated for micromeritic properties, particle size, percentage yield, in-vitro buoyancy, entrapment efficiency, drug polymer compatibility, scanning electron microscopy and in-vitro drug release studies. The prepared microspheres exhibited prolonged drug release (> 9 h) and remained buoyant for > 24 h. The mean particle size increased and the drug release rate decreased at higher polymer concentration. The optimized formulation of ethyl cellulose microspheres (KEC-OP) exhibited prolonged drug release of 88.31 % up to 10 h demonstrating zero order kinetics and Case II transport release mechanism where as optimized formulation of egg albumin (KEA-OP) showed drug release of 96.78 % up to 9 h demonstrating peppas kinetics and Case II transport release mechanism.