The O2-dependent chemotherapy usually exhibits limited therapeutic efficiency toward hypoxic solid tumors because of inadequate O2 supply in tumor vasculature. Hence, an O2-elevated nanoplatform for delivering chemotherapeutics and eradicating malignant tumors needs to be urgently developed. In this study, MnO2 nanoenzyme was coated on GSH-sensitive mesoporous silica. Subsequently, an intelligent nanoreactor was constructed after saikosaponin-d (SSD) loading in the mesopore channels and folic acid anchoring on the rough surface. After precise targeting of thyroid tumor cells, the obtained nanoreactor induced the decomposition of tumor endogenous H2O2 to relieve hypoxic tumor microenvironment. In the meantime, the tetrasulfide bonds of silica were broken by cytoplasmic GSH to release the loaded therapeutic molecules. Consequently, a remarkably enhanced chemotherapeutic effect of SSD was achieved both in vitro and in vivo. The mechanism underlying the tumor cell–killing effect was demonstrated to involve massive O2 generation, which facilitated the interruption of the PI3K/Akt signaling pathway. The outstanding biocompatibility of the H2O2/GSH dual-sensitive Mn-based nanoreactor offered an exceptional chemotherapeutic effect against malignant tumors.