Inactivation of nonpathogenic Escherichia coli in ground beef homogenate using radio-frequency (RF) heating both individually and in combination with antimicrobial treatments was investigated. Beef homogenate was prepared in phosphate buffer (pH 5.8). Inoculated beef homogenate was heated in an RF oven without antimicrobials to end-point temperatures of 50 °C resulting in 0.84 log reductions and 55 °C resulting in 0.94 log reductions. Adding antimicrobials-potassium, sodium, and ammonium bicarbonates (0.5 and 1.5%); citric acid (0.5%); potassium lactate (2.5%); and a blend of potassium bicarbonate (1.5%) and citric acid (0.5%) to the beef homogenates before RF heating did not inactivate E. coli. E. coli inactivation was also not affected in beef homogenates containing antimicrobials when heated to 50 °C in the RF oven. Heating to 55 °C did reduce E. coli more than 5 log (CFU/mL) reduction of E. coli in homogenates containing 2.5% potassium bicarbonate, 0.5% citric acid, and blends of citric acid and potassium bicarbonate at varying concentrations (0.5% citric acid + 0.5% Citric acid and 1.5% bicarbonate). This study offers scope and potential for the application of RF assisted pasteurization with antimicrobial systems as interventions to enhance the overall ground beef safety. The findings of this study should provide potential to explore industrial scale RF pasteurization of beef and other meat products while ensuring that the quality characteristics are maintained.