Radiotherapy induces DNA damage, resulting in cell-cycle arrest and activation of cell-intrinsic death pathways. However, radioresistance of some tumor entities such as malignant melanoma limits its clinical application. The innate immune sensing receptor RIG-I is ubiquitously expressed and upon activation triggers an immunogenic form of cell death in a variety of tumor cell types including melanoma. To date, the potential of RIG-I ligands to overcome radioresistance of tumor cells has not been investigated. Here, we demonstrate that RIG-I activation enhanced the extent and immunogenicity of irradiation-induced tumor cell death in human and murine melanoma cells in vitro and improved survival in the murine B16-melanoma model in vivo. Transcriptome analysis pointed to a central role for p53 which was confirmed using p53–/– B16 cells. In vivo, the additional effect of RIG-I in combination with irradiation on tumor growth was absent in mice carrying p53–/– B16 tumors, while the antitumoral response to RIG-I stimulation alone was maintained. Our results identify p53 as a pivotal checkpoint which is triggered by RIG-I resulting in enhanced irradiation-induced tumor cell death. Thus, the combined administration of RIG-I ligands and radiotherapy is a promising approach to treat radioresistant tumors with a functional p53 pathway, such as melanoma.