pH-responsive systems have attracted special research interest in drug delivery. Herein, we report a pH-responsive system based on the “COOH–Zn²⁺–drug” architecture via coordination bonding in ZnS nanospheres' mesopores. PAA-functionalized porous ZnS nanospheres were employed as cargo carriers for hosting metal ion (Zn²⁺) binders and drug molecules to form the “COOH–Zn²⁺–drug” architecture. The cleavage of either the “COOH–Zn²⁺” or the “Zn²⁺–drug” coordination bond, in response to pH variation, gives rise to a significant release of drug molecules under weakly acidic conditions (pH 5–6.5). We anticipate that the porous ZnS nanospheres and subsequently prepared pH-responsive system may prove to be a significant step toward the development of a finely pH-sensitive drug delivery system that minimizes drug toxicity.