The purpose of this research was to produce porous sponge-like PLGA microspheres through a simple emulsion technique using a non-halogenated organic solvent and methylamine. In order to achieve this objective, a dispersed phase consisting of PLGA and methyl propionate was emulsified in an aqueous polyvinyl alcohol solution to produce an oil-in-water emulsion. When methylamine was added to the aqueous phase, it partitioned to the oil phase and reacted with methyl propionate to produce methanol and N-methyl propionamide. These water-soluble decomposition products acted as anti-solvents against PLGA. As they leached to the aqueous phase, oil droplets effectively hardened to sponge-like microspheres. This technique, utilizing a chemical reaction between the dispersed solvent and methylamine, has shown excellence compared to the existing water-in-oil-in-water emulsion techniques that require the help of porogens. For example, even without using porogens and high-shear/high-energy mixing devices, our simple technology made it possible to produce very porous microspheres with a sponge-like skeleton. Also, rather than using halogenated methylene chloride, which has been commonly used to produce microspheres, this new technique used methyl propionate, a non-halogenated and safer alternative. Furthermore, it enabled us to adjust the amount of residual methyl propionate in the microspheres below 0.5%, meeting the standard of residual organic solvents in microspheres set by regulatory authorities. The innovative technology reported in this study would make a large contribution to producing porous microspheres with the use of various hydrophobic polymers.