The clinical treatment of hepatocellular carcinoma has been hindered due to the drug resistance and heterogeneity of tumor cells. A new therapy strategy combined chemo drugs and molecular-targeted drugs is considered to be promising for conquering these challenges. However, the different pharmacokinetic profiles, hydrophobicity and systemic toxicity of these drugs may still cause serious challenges to the clinical applications of this combination therapy. In this study, smart sorafenib (SF) and doxorubicin (DOX)-loaded nanodroplets (SF/DOX-NDs) were fabricated to solve the above issues. The liquid-to-gas phase transition of SF/DOX-NDs could function as a cavitation nucleus to boost drug release and increase cellular uptake after exposure to therapeutic ultrasound (TUS) irradiation. Additionally, this strategy has a therapeutic effect to induce apoptosis and inhibit the proliferation, migration, and invasion of hepatoma cells. Furthermore, the intense cavitation of SF/DOX-NDs at the tumor site could disrupt microvessels, which is beneficial for tissue-penetrating drug delivery inside tumors. Consequently, tumor angiogenesis was reduced, and tumor growth was remarkably inhibited by SF/DOX-NDs. These results indicated that combination therapy using SF/DOX-NDs may offer a promising approach to achieve effective HCC therapy with low side effects.