Microwave ablation is emerging as an effective local treatment for solid tumors. The efficiency of microwave ablation in treating hepatocellular carcinoma is evidently limited by the incomplete ablation of large tumors and tumors in high-risk locations. Microwave ablation in conjunction with localized chemotherapy is a promising strategy for cancer therapy. In this study, we prepared As₂O₃-mPEG-PLGA-PLL nanoparticles by double emulsion method and investigated their efficacy to eliminate residual cancer cells and inhibit lung metastasis after microwave ablation of hepatic VX2 tumor. As₂O₃ formulations were administered into the residual tumor area for four times over four weeks after microwave ablation (As₂O₃ equivalent to 1 mg/kg body weight). Both As₂O₃ treatments showed good therapeutic effects, including inhibiting lung metastasis and decreasing the stiffness of the residual tumors. Additionally, As₂O₃-mPEG-PLGA-PLL nanoparticles had better anti-cancer efficacy than did the As₂O₃ treatment. Compared with As₂O₃ alone, As₂O₃-mPEG-PLGA-PLL nanoparticles could increase the expression of epithelial marker E-cadherin, decrease the expression of mesenchymal markers N-cadherin and snail, as well as down-regulate the expressions of PCNA (proliferation marker), CD34 (angiogenesis marker). The As₂O₃-mPEG-PLGA-PLL nanoparticles are an effective formulation for preventing lung metastasis through reversing EMT progress after incomplete ablation, thus it has the potential to be a new therapy strategy for HCC patients.