In recent years, sonodynamic therapy (SDT) has emerged as a promising approach in biomedicine, due to its low toxicity, non-invasiveness, and deep tissue penetration for effective treatment of deep tumors. SDT utilizes ultrasound to irradiate sonosensitizers accumulated in tumors to generate reactive oxygen species (ROS), which can kill tumors by inducing apoptosis or necrosis in tumor cells. Developing safe and efficient sonosensitizers is a top priority in SDT. Recently reported sonosensitizers can be divided into three basic categories: organic, inorganic, and organic–inorganic hybrid sonosensitizers. Among these, metal–organic frameworks (MOFs) are a promising class of hybrid sonosensitizers due to their advantages of the linker-to-metal charge transfer mechanism for rapid ROS generation and the porous structure to eliminate self-quenching to increase the ROS generation efficiency. Moreover, MOF-based sonosensitizers can be combined with other therapies due to their large specific surface area, high porosity, and easy modification, which can increase the therapeutic efficacy through various synergistic effects. This review focuses on the latest progress in MOF-based sonosensitizers, strategies to improve the therapeutic effect, and the use of MOF-based sonosensitizers as multifunctional platforms for combination therapies emphasizing on increased therapeutic efficacy. Additionally, the challenges of MOF-based sonosensitizers from a clinical perspective are discussed.