The effects of drought, salinity, and combined stress on ROS and ROS metabolic physiology and transcriptomics in sweet sorghum seedling leaves were evaluated. The results showed that drought stress had little effect on photosynthesis, while the SOD activity, CAT activity, and the expression of their related genes were elevated in leaves, but no excessive accumulation of O-2 (-), H2O2, or -OH was observed. Under salinity stress, photosynthesis was inhibited, the O-2 (-), H2O2 and -OH contents increased significantly, and the SOD, POD, CAT activities and the expression of their related genes in leaves were elevated. Under combined stress, photosynthesis was significantly inhibited, the highest accumulation of O-2 (-), H2O2 and -OH contents occurred, and the SOD and POD activities and the expression of related genes in leaves were significantly increased, but the CAT was significantly decreased. These results collectively indicate that oxidative damage to sweet sorghum seedling leaves was higher with combined stress than with either drought or salinity stress alone. Under combined stress the SOD and POD activities were increased, but the CAT activity in the AsA-GSH cycle was severely reduced, demonstrating that antioxidant mechanisms in seedlings did not play a normal protective role, leaving the plants severely damaged by oxidative stress.