In order to investigate the growth of Citrullus lanatus seedlings under different concentrations of cadmium stress (0, 60, 120, 180 and 240 mg/L) and the changes of physiological characteristics and anatomical structure of leaves, and preliminary explore the physiological mechanism of watermelon tolerance to cadmium stress, we took the ‘Beikang No. 1’ as experimental material, and adopted pot experiments in laboratory. The results showed that: (1) under the condition of cadmium stress, the growth of C. lanatus seedlings was inhibited. With the increase of cadmium stress concentration, the yellowing phenomenon of C. lanatus seedlings leaf morphology gradually increased, the root morphology gradually weakened, and the plant height, stem diameter, stem node number and leaf number all showed a downward trend. (2) Under cadmium stress, the cells in the main veins of C. lanatus seedling leaves were damaged, the diameter of the main veins and the density of mesophyll tissue decreased significantly. (3) With the increase of cadmium stress concentration, the water content, net photosynthetic rate and SOD activity of C. lanatus seedlings were significantly decreased, while the malondialdehyde and free proline contents were significantly increased, the POD activity and soluble protein content were increased first and then decreased, resulting in significant effects on physiological characteristics. The results showed that the C. lanatus seedlings of ‘Beikang No.1’ had certain adaptability to cadmium. Under the low concentration (60 mg/L) cadmium stress, the morphological and physiological characteristics of C. lanatus seedlings did not change significantly, but under the high concentration (180 mg/L) cadmium stress, the growth of C. lanatus seedlings was severely inhibited, and osmotic adjustment system and biofilm protection system were seriously damaged.