Melons (Cucumis melo L.) are highly popular due to its delicate and delightful flavor in the worldwide. However, the flavor of the melon juice was easily affected by thermal treatments and unpleasant cooking smell during production process. Sugarcane (Saccharum officinarum) juice is a proven nutritious beverage with high levels of antioxidants, polyphenols, and other beneficial nutrients. Due to its low sugar content, combined with sugarcane, muskmelon-sugarcane blend juice gives an appealing and exotic drink. The research was planned to evaluate the effect of thermo-sonication (20 kHz, 70% amplitude, 5, 10 and 15 min) and microwave (90 °C, 400 W, 120 sec) on physicochemical parameters including pH, titratable acidity, total soluble solids (TSS), total phenolic contents (TPC), total flavonoid contents (TFC) and antioxidant capacity of muskmelon and sugarcane juice blend, during storage of 90 days at refrigeration (4±1 °C). The statistical results showed that synergism of sonication and microwave treatments had a significant (p ≤ 0.05) influence on pH, TSS, titratable acidity, TPC, TFC and antioxidant capacity. T3 (15 min of sonication and 120 s of microwave) showed the maximum TSS (12.00±0.40 °B), pH (5.07±0.02), TPC (484.33±10.41 mg GAE/100 mL), TFC (261.73±11.32 mg CE/100 mL), and antioxidant activity (381.62±17.72 µg AAE/100 mL), as compared to untreated samples. Thermosonication for 15 min caused maximum retention of TPC, TFC and antioxidant capacity of blend juice during 90 days of storage, whereas in untreated samples these parameters were found highly decreased during storage. Thus, sonication and microwave can be recommended as an alternative to both conventional pasteurization processes and chemical preservatives.