Ultrasonication (US) processing of ketchup, changes in its quality parameters and microbial inactivation, and joint optimization of treatment parameters (22–57.5 °C treatment temperature, 90 and 100% amplitude, and 3 and 5 min treatment times) were investigated. Increased temperature and amplitude changed properties of ketchup. Total initial mold and yeast count of 2.40 ± 0.23 log CFU/mL became undetectable with all US treatments. Total initial lactic acid bacteria of 3.91 ± 0.23 log CFU/mL became undetectable at 55 °C with 100% amplitude for 5 min and 57.5 °C with 100% amplitude for 3 and 5 min ( P < 0.05). Optimum settings were 57.39 °C, 100% amplitude, and 3.53 min (composite desirability = 0.81). The pilot-scale US treatment with a moderate temperature appeared promising to process ketchup.