Watermelon vinegar is a traditional fermented product with antioxidant activity. This study aimed to investigate the antihypertensive and antidiabetic properties of watermelon vinegar treated through ultrasound using the RSM method. We also evaluated the antioxidant activity (CUPRAC and DPPH), bioactive content (total phenolics and total flavonoids), mineral composition, phenolic compounds, α-glucosidase inhibition %, ACE inhibition %, of optimized, and α-amylase inhibition % during 24 months of storage of optimized watermelon vinegar. Optimized antidiabetic and antihypertensive activity was achieved at 6.7 min and 69% amplitude. The optimization of gallic acid was the dominant phenolic in the optimized ultrasound-treated watermelon vinegar (UT-WV) and showed a significant decrease during the 24 months of storage. The lycopene content of the UT-WV concentrate was 8.36 mg/100 mL, 8.30 mg/100 mL, 7.66 mg/100 mL, and 7.35 mg/100 mL after 0, 6, 2, and 24 months of storage, respectively. The levels of ACE inhibitory activity, α-glucosidase inhibitory activity, and α-amylase inhibitory activity decreased significantly (p < 0.05) after 24 months of storage. K, with values of 201.03 ± 28.31, was the main mineral in the UT-WV. Therefore, the bioactive components and the antidiabetic and antihypertensive properties of the UT-WV produced by conventional fermentation were necessary. Therefore, further experimental studies are necessary for a better understanding of the possible and potential health effects of watermelon vinegar.