This study investigated the effects of alprostadil combined with calcium dobesilate on the treatment of diabetic nephropathy. We recruited 80 patients with diabetic nephropathy, who were randomly divided into experimental (n=40) and control (n=40) groups. Patients received high-quality low-protein diabetic diet intervention and subcutaneous injection of insulin to adjust blood glucose, combined with antihypertensive, antiplatelet drugs, and other comprehensive treatments. The control group received alprostadil and the experimental group received alprostadil combined with calcium dobesilate. Both groups were treated for 12 weeks as one treatment cycle. The time to remission of clinical symptoms such as mental fatigue and weakness, limb edema, soreness and swelling of waist and knee, cold limbs and limb numbness and pain was significantly shorter in the experimental group than that in the control group (p<0.05). After intervention, the blood levels of small molecular weight proteins, such as β2-microglobulin (β2-MG), cystatin C (CysC), and retinol binding protein (RBP), were significantly lower in the experimental group than those in the control group (p<0.05). The levels of the inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and C-reactive protein (CRP) were significantly lower in the experimental group than those in the control group (p<0.05). The levels of 25-hydroxyvitamin D and parathyroid hormone were significantly higher in the experimental group than those in the control group (p<0.05). The level of angiotensin II was lower in the experimental group than that in the control group (p<0.05) and the level of fasting serum insulin was significantly higher in the experimental group than that in the control group (p<0.05). The homeostasis model assessment of insulin resistance (HOMA-IR) index was lower in the experimental group than that in the control group (p<0.05). The levels of renal function indexes, blood urea nitrogen, creatinine and uric acid, in experimental group were lower than those in control group (p<0.05). The levels of brain derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1) were significantly higher in both groups after the intervention than those before the intervention (p<0.05). The levels of BDNF and IGF-1 were higher in the experimental group than that in control group after intervention (p<0.05). The application of alprostadil combined with calcium dobesilate in patients with diabetic nephropathy can effectively relieve clinical symptoms, improve renal functions, reduce blood levels small proteins, alleviate the inflammatory response, and regulate the levels of BDNF and IGF-1, thus improving the clinical treatment effect.