Glutathione (GSH), a tripeptide abundant in the cancer cells, inhibits the cytotoxic effect of reactive oxygen species (ROS) and is associated with anti-apoptosis, thus facilitating tumor growth. Here, we report GSH-depleting carboxymethyl dextran nanocomposites for chemo-sonodynamic therapy for cancer. The nanocomposite is composed of the TiO2-based core as the sonosensitizer, MnO2 coat as the GSH-consuming chemosensitizer, and carboxymethyl dextran as the hydrophilic shell. The in vitro cell experiments demonstrated that, when taken up by the cancer cells, the nanocomposites can deplete intracellular GSH by reducing MnO2 to Mn2+ which induces intracellular ROS production. Upon exposure to ultrasound, the nanocomposites effectively generated cytotoxic singlet oxygen at the intracellular level, remarkably enhancing the cytotoxicity to cancer cells. Notably, chemo-sonodynamic activity of the nanocomposites induced apoptosis as well as necrosis of cancer cells, implying their high potential as the anticancer therapeutics. Display omitted •Carboxymethyl dextran-based hybrid nanocomposites (MTNCs) were developed for chemo-sonodynamic therapy of cancer.•MnO2 in MTNCs depleted upregulated glutathione and produced Mn2+ to generate hydroxyl radicals in cancer cells.•TiO2 in MTNCs generated single oxygen in the presence of ultrasound.•Chemo-sonodynamic activity of MTNCs induced apoptosis as well as necrosis of cancer cells.