Background In 2021, approximately 537 million adults globally had diabetes, with projections estimating an increase to 643 million by 2030 and 783 million by 2045. Uncontrolled diabetes can cause severe complications, including diabetic nephropathy, a prevalent microvascular disease and a primary contributor to end-stage renal failure, with an increasing mortality rate. Methods Conduct a search for randomized controlled trials (RCTs) on the use of prostaglandins in treating diabetic nephropathy across PubMed, Cochrane Library, Web of Science, CNKI, and Wanfang databases. Two researchers will independently screen the retrieved literature, assess the methodological quality using the bias risk assessment tool from the Cochrane 5.1 manual, and conduct statistical data analysis. Results A total of 1019 patients were included in 11 studies. The meta-analysis results show the effective rate of the test group, which was significantly higher (P < 0.01, OR 1.32; 95% CI 1.13-1.55) than the control group.24-h urinary protein quantification of the test group was lower (P < 0.01, SMD - 2.12; 95% CI - 3.26 to - 0.99). The test group exhibited significantly lower levels of blood creatinine (P < 0.01, SMD - 0.99; 95% CI - 1.42 to - 0.57) and blood urea nitrogen (P < 0.01, SMD - 0.93; 95% CI - 1.34 to - 0.51). Conclusion The findings suggest that prostaglandins enhance the effective rate and improve 24-h urinary protein quantification, blood creatinine, and blood urea nitrogen levels in diabetic nephropathy patients.