Sonodynamic therapy (SDT) has been recognized as a spatial-temporal and noninvasive modality for the treatment of deep-seated tumors. However, current sonosensitizers suffer from low sonodynamic efficacy. Herein, we reported the design of nuclear factor kappa B (NF-κB) targeting sonosensitizers (TR1, TR2, and TR3) by integrating a resveratrol motif into a conjugated electron donor-acceptor (triphenylamine benzothiazole) skeleton. Among these sonosensitizers, TR2 with two resveratrol units in one molecule was the most potent for inhibiting NF-κB signaling. Owing to the synergy of high sonodynamic efficacy and NF-κB activation inhibition, TR2 displayed a remarkable sonocytotoxicity to MCF-7 breast cancer cells. Xenograft mice studies demonstrated that TR2 had excellent anticancer potency and biosafety. This study thus opens up a new avenue for the development of efficient organic sonosensitizers for cancer ablation.