Diabetes nephropathy (DN) is one of the most prevalent microvascular complications of Diabetes Mellitus (DM). The present study was carried out to explore the role of roflumilast, a PDE4 inhibitor, as a potential treatment option for DN. The model was developed by feeding a high-fat diet for four weeks and following streptozotocin (30 mg/kg) injection intraperitoneally. The rats with >13.8 mmol/L blood glucose were included in the study. The diabetic rats were treated with roflumilast (0.25, 0.5, 1 mg/kg) and standard metformin (100 mg/kg) orally once a day for eight weeks. Roflumilast (1 mg/kg) remarkably improved renal damage, which was indicated by an increase in 16% albumin, a decrease in 5% serum creatinine, 12% BUN, 19% HbA1c, and 34% blood glucose. It also significantly improves the oxidative stress levels, which was indicated by a decrease in 18% MDA level and an increase in GSH, SOD, and catalase by 6%, 4%, and 5%, respectively. Roflumilast (1 mg/kg) decreased the HOMA-IR index by 28% and increased the pancreatic β-cells functioning by 30%. Moreover, significant improvement in histopathological abnormalities was observed in roflumilast treatment groups. Roflumilast treatment was shown to down-regulate the gene expression of TNF-α, NF-kB, MCP-1, fibronectin, and collagen IV, and upregulated the expression of the Nrf2 gene. The gene expression was significantly reduced by 2.1-fold, 2.3-fold, 2.5-fold, 2.7-fold, and 1.52-fold individually. The Nrf2 gene was upregulated by 1.43-fold. These results manifested that roflumilast alleviated renal injuries in DN rats, which might be associated with suppressing the JAK/STAT signaling pathway.