Sustained-release micro-/nanospheres of the ketorolac tromethamine (KTC) were prepared using four different techniques viz., single emulsion solvent evaporation, high pressure homogenization, spray drying, and using a microreactor. Ethyl cellulose (EC) was used as an encapsulating agent for the preparation of sustained-release micro-/nanospheres of KTC. The Plackett-Burman design was employed for design of the experiments. The resulting micro-/nanospheres were characterized for their size, morphology, encapsulation efficiency, and in vitro drug release performance. Interactions between the KTC and EC were quantified by Fourier transform infrared (FTIR) spectroscopy and X-ray powder diffractometry (XRPD). Particle morphology characterization was performed using field emission scanning electron microscopy. The micro-/nanospheres showed encapsulation efficiency of 42.34-89.33% by the solvent evaporation technique, 76.36-91.13% by the high-pressure homogenization technique, 70.74-79.68% by spray drying, and 79.00-89.49% by the microreactor technique. The micro-/nanospheres were found to be spherical and oval with smooth surface. The FTIR analysis confirmed no interaction of KTC with EC polymer. The XRPD analysis revealed good dispersion of the drug within the micro-/nanospheres formulation. Sustained KTC release profile over 12 h was achieved successfully by EC polymer. In conclusion, EC sustained-release micro-/nanospheres containing KTC can be prepared successfully using different techniques.