Hyperglycemia refers to a condition in which an excessive amount of glucose circulates in the blood plasma. A wide range of evidence has proved hyperglycemia to be a great inducer of reactive oxygen species (ROS), through which various processes and signaling transduction cascades are activated or inhibited. Bursts of ROS can be produced by mitochondria, NADPH oxidase, and xanthine oxidase under hyperglycemia. These excessive ROS will further cause oxidative stress and contribute to the development of hyperglycemia complications. One of the downstream processes affected by redox imbalance is autophagy. Increasing evidence shows disturbed autophagy in cell lines treated with high glucose or in animals under hyperglycemia. The signaling pathways involved in are quite controversial, however. Here, we focus on the ROS-ERK/JNK-p53 pathway and discuss its potential role in activating autophagy in the condition of hyperglycemia.