Piezoelectric materials produce charges to directly act on cancer medium or promote the generation of reactive oxygen species (ROS) for novel tumor therapy triggered by sonography. Currently, piezoelectric sonosensitizers are mainly used to catalyze ROS generation by the band-tilting effect for sonodynamic therapy. However, it remains a challenge for piezoelectric sonosensitizers to produce high piezovoltages to overcome the bandgap barrier for direct charge generation. Herein, Mn-Ti bimetallic organic framework tetragonal nanosheets (MT-MOF TNS) are designed to produce high piezovoltages for novel sono-piezo (SP)-dynamic therapy (SPDT) with remarkable antitumor efficacy in vitro and in vivo. The MT-MOF TNS comprise non-centrosymmetric secondary building units of Mn-Ti-oxo cyclic octamers with charge heterogeneous components for piezoelectricity. The MT-MOF TNS promotes strong sonocavitation to induce piezoelectric effect with a high SP voltage (2.9 V) in situ, to directly excite charges, which is validated by SP-excited luminescence spectrometry. The SP voltage and charges depolarize the mitochondrial and plasma membrane potentials and cause ROS overproduction and serious tumor cell damage. Importantly, MT-MOF TNS can be decorated with targeting molecules and chemotherapeutics for more severe tumor regression by combining SPDT with chemodynamic therapy and chemotherapy. This report develops a fascinating MT-MOF piezoelectric nano-semiconductor and provides an efficient SPDT strategy for tumor treatment.