Intratumoral immunotherapy (ITIT) delivers immune-stimulating agents or treatments directly into solid tumors to reverse the immunosuppressive nature of the tumor microenvironment (TME) and enables local and systemic antitumor immunity. However, optimal clinical strategies for ITIT are not yet fully understood. Cowpea mosaic virus (CPMV) is a plant virus that is not infectious in mammals but is a powerful multi-toll-like receptor (TLR) agonist which stimulates potent antitumor immunity when used in ITIT. ITIT by transfection of interleukin-12 (IL-12) expressing plasmids into melanoma tumors electroporation is being assessed in Phase II clinical trials to treat metastatic disease. We investigated the combination of CPMV with IL-12 plasmid electroporation to generate systemic (abscopal) immunity superior to that from either monotherapy alone. Mice were inoculated with two B16-F10 melanoma or MC38 colorectal cancer tumors and one tumor on each flank. One tumor was treated once per week for 2 weeks with IL-12 electroporation and CPMV intratumoral injection. IL-12 electroporation following CPMV injection greatly reduced the efficacy of CPMV by disrupting its viral structure. Conversely, electroporation of IL-12 prior to CPMV injection led to total clearance of 100% of treated tumors and significantly greater suppression of distant, untreated tumors compared to either monotherapy or the reverse treatment order (CPMV IT injection, followed by IL-12 electroporation). This superior abscopal effect led to a significantly improved survival. Our novel treatment strategy offers significant translational value in treating solid tumors by improving the local and systemic efficacy of IL-12 electroporation or CPMV alone.