Thermosonication (TS) has been identified as a smart remedy for the shortcomings of heat treatment, which typically requires prolonged exposure to high temperatures. This technique combines moderate heat treatment with acoustic energy to eliminate harmful microorganisms and enzymes in food products. Unlike conventional heat treatment, thermosonication utilizes short holding times, allowing for the preservation of food products’ phytochemical compounds and sensory characteristics. The benefits and challenges of this emerging technology, such as equipment cost, limited availability of data, inconsistent results, high energy consumption, and scale-up challenges, have been assessed, and the design process for using ultrasound in combination with mild thermal treatment has been discussed. TS has proven to be a promising technique for eliminating microorganisms and enzymes without compromising the nutritional or sensory quality of food products. Utilizing natural antimicrobial agents such as ascorbic acid, Nisin, and ε-polylysine (ε-PL) in combination with thermosonication is a promising approach to enhancing the safety and shelf life of food products. Further research is required to enhance the utilization of natural antimicrobial agents and to acquire a more comprehensive comprehension of their impact on the safety and quality of food products.