The facultative anaerobe Salmonella strain VNP20009 selectively colonizes into tumors following systemic injection due to its preference for the hypoxia in the tumor cores. However, the phase 1 clinical trial of VNP20009 has been terminated mainly due to its weak antitumor effects and exhibition of dose-dependent toxicity. Here, we leveraged the advantages of VNP20009 biotherapy together with polydopamine-mediated photothermal therapy in order to enhance the antitumor efficacy toward malignant melanoma. VNP20009 was coated with polydopamine via oxidation and self-polymerization, which was then injected into tumor-bearing mice via the tail vein. Polydopamine-coated VNP20009 targeted hypoxic areas of the solid tumors, and near-infrared laser irradiation of the tumors induced heating due to polydopamine. This combined approach eliminated the tumors without relapse or metastasis with only one injection and laser irradiation. More importantly, we found both VNP and pDA potentiate the therapeutic ability of each other, resulting in a superior anticancer effect.