Objective To systematically review the efficacy of total glycosides extracted from Rehmannia glutinosa Libosch leaf in the treatment of diabetic nephropathy. Methods Databases including PubMed, EMbase, MEDLINE, The Cochrane Library, Web of Science, CNKI, WanFang Data and VIP were electronically searched to collect randomized controlled trials of total glycosides from Rehmannia glutinosa Libosch for diabetic nephropathy from inception to May 30th, 2021. Two reviewers independently screened literature, extracted data, and assessed the risk of bias of included studies. RevMan 5.4 software was then used to perform meta-analysis. Results A total of 7 RCTs involving 504 patients were included. The results of meta-analysis showed that there were no significant differences in creatinine levels (MD=−1.71, 95%CI −3.97 to 0.56, P=0.14) and urea (MD=−0.18, 95%CI −0.44 to 0.08, P=0.19) between the two groups. In terms of regulating proteinuria, the urinary albumin excretion rate (MD=−39.41, 95%CI −48.46 to −30.36, P<0.000 01), urinary microalbumin (MD＝−9.94, 95%CI −12.16 to −7.73, P<0.000 01), and 24-hour urinary protein (MD=−0.67, 95%CI −0.85 to −0.49, P<0.000 01) were all lower in the treatment group compared with control group. However, there were no differences between groups in terms of blood glucose metabolism as indicated by changes in levels of the long-term blood glucose metabolism indicator (HbA1c: MD=−0.16, 95%CI −0.67 to 0.35, P=0.53). Only one study suggested that short-term blood glucose metabolism indicators, fasting blood glucose and postprandial blood glucose levels were not different between groups. In terms of blood lipid metabolism, only one study suggested glycoside treatment produced lower serum levels of cholesterol and triglycerides compared with control group. Conclusions Current evidence suggests that adjunctive therapy with total Rehmannia glutinosa Libosch glycosides can benefit diabetic nephropathy patients more than angiotensin II receptor inhibitor or pancreatic kininogen by alleviating proteinuria and likely improving lipid metabolism. However, no benefit is observed in terms of renal function improvement or blood glucose metabolism. Due to limited quality and quantity of included studies, more high-quality studies are required to verify the above conclusions.