Ferroptosis is a newly detected iron-dependent form of regulated cell death. Sono-photodynamic therapy (SPDT) can generate reactive oxygen species (ROS) and induce cell death under light and ultrasound. Due to the complexity of tumor physiology and pathology, single-modality often fails to achieve a satisfactory therapeutic effect. The development of a formulation platform with integration of multiple therapeutic modalities using a simple and convenient method is still a challenge. Here, we report the facile construction of a ferritin-based nanosensitizer FCD by co-encapsulating chlorin e6 (Ce6) and dihydroartemisinin (DHA) in horse spleen ferritin, and was employed for synergistic ferroptosis and SPDT. Ferritin in FCD can release Fe under acidic conditions and Fe can be reduced to Fe in the presence of glutathione (GSH). The Fe can react with hydrogen peroxide (HO) to produce harmful hydroxyl radicals. Furthermore, a large amount of ROS can be generated the reaction of Fe with DHA and by simultaneously irradiation of FCD with both light and ultrasound. More importantly, the depletion of GSH by FCD could decrease glutathione peroxidase 4 (GPX4) and increase lipid peroxidation (LPO) levels, thereby inducing ferroptosis. Therefore, by integrating the advantageous GSH-depletion capacity, ROS generation ability, and ferroptosis induction capability into one single nanosystem, FCD can serve as a promising platform for combined chemo-sono-photodynamic therapy of cancer.