This study examined the efficacy of continuous flow high-pressure homogenization (CFHPH) under varying pressures, inlet temperatures, and flow rates, in preserving the nutritional quality and stability of watermelon juice during simulated market conditions and compared it with traditional high-temperature short-time (HTST) processing. The retention of ascorbic acid, carotenoids, and amino acids was analyzed using liquid chromatography, while PPO (polyphenol oxidase) and POD (peroxidase) enzyme activity was assessed using a UV–vis spectrophotometer.We observed a significant decrease (p ≤ 0.05) in ascorbic acid levels after 15 days of storage. For carotenoids, the impact was influenced by the interaction of pressure, flow rate, and inlet temperature within CFHPH, with no clear trend emerging regarding their preservation over 45 days of storage at 4 °C. However, overall retention of carotenoids surpassed that of HTST samples. Both methods enhanced free amino acid contents significantly and decreased PPO and POD activity, with HTST being slightly more effective. Ornithine and histidine concentrations significantly increased, with up to a fourfold rise in samples treated with 300 MPa pressure and up to a tenfold rise for HTST at 95 °C after 45 days of storage. This study suggests optimizing the CFHPH process to enhance the shelf-life and nutritional value of watermelon juice, offering consumers a healthier and longer-lasting choice. Industrial relevanceOur findings highlight CFHPH's higher retention of bioactive compounds, reduction in degradative enzyme activity, and enhancement of the amino acid profile, making it a compelling choice for the fruit juice processing industry. Despite the energy-intensive nature of CFHPH, its ability to preserve vital bioactive compounds like carotenoids and ascorbic acid addresses the growing consumer demand for nutritious and stable juice options. The benefits of CFHPH in maintaining juice quality and nutritional value may outweigh the associated energy costs, making it a promising technology for fruit juice processing.