The topical consumer interest for natural, healthier, safer and nutritinal juice, has intrigued the search for innovative technologies that can minimize product degradation. In this regard, thermosonication has been proposed as a potential processing technology that can inactivate microorganisms, and enzymes and produce fresh-like products. In line with this, watermelon (Citrullus lanatus) juice is one of the common fruit juices that is desired by consumers due to its desirable color, pleasant odor, sweet taste and low calories. However, this fruit juice is highly perishable and is thermo-sensitive, it degrades quickly under thermal processing. Therefore, this study aimed to identify optimal thermosonication processing conditions to retain the critical quality parameters of watermelon juice. Response surface methodology (RSM) employing a central composite design was used to determine the effects of temperature (25–52ºC), processing time (2–10 min) and amplitude level (24–60 µm) to retain the quality parameters (total polyphenolic content, lycopene, β-carotene and ascorbic acid) of watermelon juice. The optimum conditions obtained were 125ºC, 2 min, and 24 µm and were experimentally validated. These conditions resulted in lycopene of 7.4 mg/100 g, β-carotene of 0.15 mg/100 g, ascorbic acid of 2.86 mg/100 g and total polyphenolic content of 21.32 mg/100 mg/ GAE with desirability of 0.81. The proposed model was adequate (p < 0.0001) with a satisfactory determination coefficient (R2) less than 0.8 for all phytochemicals. The proposed conditions provided better preservation of the quality characteristics of watermelon juice.