Cefixime trihydrate is an orally active third generation cephalosporin having a wide range of activity. But its bioavailability is limited to about 40-50% after oral administration. The development of floating microspheres is a possible alternative to overcome this problem. The floating microspheres of cefixime were prepared with this objective using the biocompatible natural polymers like alginate and chitosan by ionotropic gelation method. A 3 2 full factorial experiment was designed to study the effect of independent variables such as alginate and chitosan concentration. The response parameters investigated are buoyancy and cumulative drug release percentage and was statistically analyzed by applying ANOVA. Contour plots and three-dimensional surface response plots were drawn to evaluate the interaction of the independent variables on the chosen dependent variables. Two optimal formulations were developed by setting the constraints on the independent variables to maximize the buoyancy and drug release percentage. The values of the observed responses are compared with those predicted by the mathematical models along with the % prediction errors. The low value of error proved the ability of response surface methodology to predict the behavior of the drug-loaded floating microspheres. Surface morphology of the microspheres was studied by SEM analysis. Kinetic studies reveal that the optimized formulations release the drug in the zero order manner with non-Fickian diffusion mechanism based on the regression values of zero order, Higuchi, and Korsmeyer-Peppas model.