A biodegradable silica was fabricated to achieve effective tumor microenvironment responsive drug delivery with low drug leakage (4%, 80 h) and good biosafety. A disulfide bond embedded copolymer composited by methylacrylic acid (MAA) and vinyl trimethoxysilane was utilized for the in situ synthesis of the PMAA hybrid biodegradable silica shell. The biodegradable silica was introduced as a gatekeeper to alter the drug release behavior of the doxorubicin‐loaded in the mesoporous silica microspheres. The fabrication process and glutathione‐responsive degradation of the drug delivery system were carefully studied. In vitro drug release experiments revealed that 65% of the loaded drug could be released after 80 h in simulated tumor environment. The biocompatibility of the carrier and the anti‐cancer efficiency against the HepG2 cancer cell line were studied with the cell counting kit‐8 assay. The method to prepare the biodegradable silica reported in this work might provide new thought to the fabrication of high‐performance drug delivery systems.