<p><i>Citrullus lanatus</i> is an important vegetable crop, but it is heavily polluted by cadmium. In this study, we used <i>C. Lanatus</i> as experimental material to investigate effects of different concentrations (0, 50, 100, 200, 400&#xa0;µmol^.L⁻¹) of exogenous melatonin, and grafting on the physiological growth index and anatomical structure of seedlings were studied by simulating Cd²⁺ (180&#xa0;mg L⁻¹) stress environment. The results showed that exogenous melatonin could reduce the injury degree of <i>C. Lanatus</i> seedlings under cadmium stress, and the best effect was obtained when the concentration is 100&#xa0;µmol^.L⁻¹. Compared with the control treatment (0&#xa0;µmol^.L⁻¹ melatonin), the number of leaves treated with 100&#xa0;µmol^.L⁻¹ melatonin increased by 32.61%, the density of mesophyll tissue decreased by 16.47%, the relative content of chlorophyll in seedling leaves increased by 42.90%, and the activity of superoxide dismutase (SOD) and the content of soluble protein increased by 28.64% and 60.11%, respectively. In addition, grafting could effectively alleviate the damage of cadmium stress to <i>C. lanatus</i> seedlings, and the effect of 100&#xa0;µmol^.L⁻¹ melatonin and grafting interaction on seedlings was higher than that of single melatonin or grafting treatment. Under cadmium stress, compared with the self-rooted seedlings of melatonin (0&#xa0;µmol^.L⁻¹), the stem diameter and the diameter of main vein increased by 55.56% and 34.12%, and the water content of leaf tissue increased by 93.55%. In addition, the relative conductivity and MDA content decreased by 54.45% and 53.07%, respectively. Therefore, there was a significant interaction between exogenous melatonin and grafting in alleviating the injury of <i>C. lanatus</i> seedlings under cadmium stress. Our research explored the optimal concentration of exogenous melatonin to alleviate the injury of <i>C. lanatus</i> seedlings under cadmium stress that provided theoretical basis for revealing the mechanism of exogenous melatonin to improve the resistance of <i>C. lanatus</i> to cadmium stress.</p>