Hollow mesoporous silica spheres (HMSS) have a hierarchical mesoporous structure composed of a hollow cavity and mesoporous shell available for high capacity drug storage. The covalent attachment of ZnO quantum dots (QDs) to the HMSS outer surface as gatekeepers via disulfide-conjugated two amide linkages encapsulated the anticancer drugs doxorubicin (DOX) within the HMSS cavities and pores, and minimized premature release of the drug. The controlled release of the drug from the ZnO-gated HMSS delivery system was realized by the dissolution of ZnO QDs upon a decrease in pH and cleavage of the disulfide bonds, which indicates that the pH- and redox-responsive controlled release of the drugs could be synergically stimulated by tumor cells with weakly acidic environments and high-expressed glutathione. The constructed ZnO-gated HMSS delivery system has promising applications in site-specific drug release for tumor chemotherapy.