The inactivation of Salmonella on cantaloupes using hot water was investigated. Whole melons, inoculated with a cocktail of Salmonella isolates, were subjected to thermal treatments of various lengths in water at 65 °C, 75 °C, and 85 °C. Treatment with water at 85 °C for 60 and 90 s resulted in reductions of up to 4.7 log colony forming units (CFU) per square centimeter of rind. However, the rind of melons treated at 85 °C for 90 s were noticeably softer than the rind of melons treated for 60 s. Thermal penetration profiles were measured and computer simulations were conducted to verify the effect of hot water treatment conditions on the internal temperatures of cantaloupe melons. Experimental and simulation data indicated that the internal temperature of melons treated with hot water did not increase rapidly compared with the rind temperature. Regardless of the process temperature used, the temperature of the edible flesh, 10 mm from the surface of the rind, remained at least 40 °C cooler than the surface temperature of cantaloupe melons. These results demonstrate the utility of hot water for the inactivation of Salmonella on cantaloupes and provide a framework to producers of fresh-cut melon for the potential use of hot water as an intervention treatment.