The objectives of this study were to apply a base-driven reaction to developing a new microencapsulation technique to prepare progesterone-containing poly-D,L-lactide-co-glycolide microspheres. Nonhalogenated ester solvents such as ethyl acetate and ethyl formate were used as dispersed solvents. After an oil-in-water emulsion was prepared, a sodium hydroxide solution was added to trigger base-catalyzed hydrolysis of organic solvents dissolved in the aqueous phase. Their rapid depletion provided a sink condition and drove the continual diffusion of the organic solvents residing in emulsion droplets into the aqueous phase. These events led to the solidification of emulsion droplets into microspheres over 15-30 min, without the use of a quenching liquid. The rate of the base-driven reaction observed with ethyl formate was 2.3 times faster than that attained with ethyl acetate. The drug encapsulation efficiency was ≥93.2%, and solvent residues in the microspheres ranged from 1.87 to 2.69%. GPC and FTIR results demonstrated that the structural integrity of the polymer and progesterone remained unchanged during the base-catalyzed microencapsulation process. This method might serve as a promising alternative for preparing nanoparticles and microspheres.