Multidrug resistance (MDR) of cancer stem cells (CSCs) is a major hurdle to chemotherapy, and it is very important to develop CSCs-specific targeted nanocarriers for the treatment of drug resistant CSCs. In this work, we developed CSCs-specific targeted mSiO2-dPG nanocarriers simultaneous delivery chemotherapy drug DOX along with the P-glycoprotein (P-gp) inhibitor tariquidar (Tar) for enhanced chemotherapy to overcome MDR in breast CSCs. The mSiO2-dPG nanocarriers possess a high loading capability, excellent pH stimuli-responsive performance, and good biocompatibility. With the help of CSCs-specific targeting and P-gp inhibitor Tar, the accumulation of DOX delivered by the mSiO2-dPG nanocarriers could be greatly increased in drug resistant three-dimensional mammosphere of breast CSCs, and the chemotherapeutic efficacy against breast CSCs was enhanced. Moreover, the expression of stemness-associated gene and tumorspheres' formation ability was also significantly suppressed, which indicates the excellent capability for overcoming MDR of breast CSCs. Taken together, we developed a CSCs-specific targeted mSiO2-dPG nanocarriers for co-delivery DOX and Tar, which provide a promising approach to effectively eliminate the CSCs and overcome the MDR of breast CSCs.