The aim of the present study was to prepare and evaluate colon-specific microparticles of piroxicam by oil/water emulsion solvent evaporation method. A 32 factorial design was employed to study the combined influence of two independent variables amount of piroxicam (X1) and amount of eudragit S-100 (X2) on dependent variables, encapsulation efficacy (Y1), percentage cumulative drug release at the fifth hour (Y2), and percentage cumulative drug release at the tenth hour (Y3). The microparticles were evaluated for micromeritic properties and drug release studies. Drug–polymer interaction was determined by differential scanning calorimeter, x-ray powder diffraction. The surface morphology and spherocity was studied by scanning electron microscopy. The developed piroxicam microparticles showed desired colon-specific delivery.