Iodine (I) is a crucial micronutrient for human health, as its insufficient intake can lead to various health problems, such as thyroid dysfunction. Although not essential for terrestrial plants, I can act as a biostimulant at appropriate concentrations, promoting good crop productivity and metabolism changes. This study aimed to investigate the effects of foliar spray of I on melon yield, antioxidant compounds, and their accumulation in fruits. The experiment involved applying different doses of I (0, 5, 10, 15, and 20 µM/L) every 15 days after transplanting. Results showed that low doses of I (5 µM/L) improved melon yield and commercial quality, while high doses (20 µM/L) decreased yield and commercial quality, but increased the biosynthesis of bioactive compounds and I on the fruits. Therefore, plant biofortification is an important technique to increase I concentrations in crops and produce functional foods with potential health benefits.