The consumption of plant-based dairy alternatives has increased rapidly around the world as a result of numerous positive health effects. Little information is available about the potential use of watermelon seed milk in the manufacture of yoghurt. The present study was undertaken to investigate the remedial action of yoghurt enriched with watermelon seed milk in renal injured hyperuricemic rats. A new yoghurt, substituting cow’s milk with different proportions of watermelon seed milk was prepared, followed by evaluation of its acceptability and functionality. Four different types of yoghurt were prepared from cow’s milk containing 3% fat, with different proportions of blended watermelon seed milk (0.0, 25, 50 and 75%). Sensorial traits, i.e., appearance, flavor, body and texture, and overall acceptability demonstrated that the blended treatment (50% cow’s milk and 50% watermelon seed milk.) was the most acceptable. This blend was then tested as an anti-hyperuricemia agent in rats. In this respect, twenty-four male albino rats were assigned into four groups (n = 6). The first group was solely administered a standard diet, and served as the negative control. The other rats (n = 18) received a basal diet including 20 g/kg dietary potassium oxonate in order to induce hyperuricemia. The hyperuricemic rats were then divided into three groups; the first group did not receive any treatment and served as the positive control, while the second and third groups were administered 10% cow’s milk yoghurt and 10% watermelon seed milk yoghurt, respectively. Interestingly, the results showed that the hyperuricemic group receiving a diet supplemented with 10% watermelon seed milk yoghurt was not significantly different from the negative control in the measured biological parameters, and saw a significant improvement in renal function compared to the positive control. The biologically favorable action of watermelon seed milk yoghurt could be attributed to its potential promotion of antioxidant status via enhancement of the activities of superoxide dismutase, catalase, and glutathione transferase. Collectively, this study concluded that watermelon seed milk can be used in yoghurt manufacturing in proportions of up to 50%, and may improve kidney function as an anti-hyperuricemic agent.