Sonodynamic therapy (SDT) represents a promising modality that provides the possibility of non-invasively eliminating solid tumors in a site-directed manner. In light of the complexity and heterogeneity of tumors, more and more studies are attempting to combine SDT with other therapeutic methods so as to achieve better tumor treatment effect, which sheds new light on the potential of SDT-based synergistic therapeutics. Herein, the representative studies of SDT-instructed multimodal synergistic cancer therapy are comprehensively presented, such as sono-chemotherapy, sono-radiotherapy, sono-immunotherapy, and sono-chemodynamic therapy, etc., and their incorporate mechanisms are discussed in detail. The current challenges and future prospects to promote the advanced development of SDT-based nanomedicines in this burgeoning research field are highlighted. It is believed that such an emerging synergistic therapeutic modality based on SDT will play a more significant role in the field of tumor precision treatment medicine.