Piroxicam-CMSC solid dispersions were produced by spray drying from aqueous solvents. Depending on the drug-polymer ratio, loading and entrapment efficiency of CMSC microparticles were 6.8–46.75 and 40.79–60.35% w/w, respectively. Scanning electron microscopy revealed non-spherical geometry and agglomeration of the spray-dried particles. The average size of the particles ranged from 7 to 170 µm. Infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction confirmed intact crystalline piroxicam in the microparticles. In gastric pH, microparticles and native piroxicam have shown less than 25% and more than 45% of drug dissolution, respectively in 2 h. In contrast, at pH 7.4, microparticles have shown 80% of drug dissolution; whereas native piroxicam achieved only 30% of dissolution by 30 min. The spray-dried CMSC particles are efficient in restricting drug release in gastric pH and enhance drug dissolution in intestinal pH. The method is eco-friendly as it uses aqueous solvents and non-toxic materials.