Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease worldwide, and podocyte ferroptosis plays a crucial role in its pathogenesis. Hirsutine (HS) reduces blood glucose levels and improve insulin resistance in diabetic mice, suggesting its potential use in diabetes treatment. Here, we established a db/db mouse model of DKD and administered HS for 8 weeks. We found that HS decreased the concentrations of iron, reactive oxygen species (ROS), and malondialdehyde (MDA) in renal tissues. Furthermore, HS treatment restored mitochondrial morphology, increased Glutathione Peroxidase 4(GPX4) levels, and decreased p53 levels, alleviating podocyte loss in the DKD mouse model. However, the effects of HS were reversed by the p53 activator Nutlin-3. Therefore, we propose HS may mitigate podocyte injury in DKD by regulating the p53/GPX4 pathway, providing a novel strategy for targeting podocyte ferroptosis in DKD.