The objective of this study was to develop a new oil-in-water emulsion template for the preparation of highly porous poly(lactide-co-glycolide) (PLGA) microspheres having a spongelike skeleton and a pore-closing functionality. A dispersed phase consisting of isopropyl formate and PLGA was emulsified in an aqueous phase. Ammonia was added toward this emulsion, in order to induce ammonolysis in the dispersed phase. Subsequently, isopropyl formate was broken into water-soluble isopropanol and formamide. As they functioned as anti-solvents against PLGA, microsphere hardening occurred. Also, their leaching into the aqueous phase led to the formation of highly porous, spongelike microspheres. The microsphere porosity was found to be controlled by adjusting isopropyl formate volume, PLGA type and concentration, ammonia volume, and ammonia–isopropyl formate molar ratio. When these dried microspheres were dispersed into an aqueous phase, the pores closed themselves autonomously. Herein, the self-closing capability of the microspheres was greatly influenced by microsphere Tg and the aqueous phase temperature. FITC-dextran and lysozyme were successfully encapsulated into the microspheres by simply equilibrating their aqueous solutions with the self-closing microspheres. In conclusion, the new emulsion template did not use either a halogenated organic solvent or conventional porogens. It did not require high-shear or high-energy mixing devices that must be used in the practice of most contemporary microencapsulation techniques. Despite these facts, this new technique was able to fabricate spongelike microspheres with an extremely high porosity and an outstanding pore-closing functionality.