It is well known that hyperglycemia leads to the progression and expansion of various micro and macrovascular disease such as diabetic nephropathy (DN). Lycoperoside H (LH) alkaloidal saponin exhibited the antidiabetic effect, but its DN effect is unclear. In this experimental study, we scrutinized the renal protective effect of LH against the streptozotocin (STZ)-induced DN in rats and explore the underlying mechanism. Sprague–Dawley rats were used in this experimental study and an intraperitoneal injection of STZ (45 mg/kg) was used for the induction of diabetes, rats received the oral administration of LH (20 mg/kg). The blood glucose level, body weight, organ weight (renal and pancreas), and biochemical parameters were estimated. We also scrutinized the effect of LH to enhance intestinal barrier function and suppress inflammation and intestinal permeability. LH significantly (p < 0.001) decreased the glucose level and enhanced the body weight with a reduction of renal weight and boost the pancreas weight. LH significantly (p < 0.001) enhanced the creatinine level and decreased the albumin level, urine volume, urinary albumin excretion rate, and urinary albumin creatinine ratio in the urine. It also suppressed the renal parameters, such as creatinine, blood urea nitrogen, and urea. LH significantly (p < 0.001) altered the level of lipid and antioxidant parameters. LH treatment significantly (p < 0.001) suppressed the cytokines and inflammatory parameters. LH considerably enhanced the Ruminococcaceae, Blautia, and suppressed the abundance of Bifidobacterium, Clostridium, and Turicibacter. It reduced the F/B ratio along with alteration of community abundance of Firmicutes, Actinobacteria, Proteobacteria, Tenericutes, other bacteria, and Bacteroidetes. The current result suggests that LH suppressed the diabetic nephropathological condition via alteration of gut microbiota and inflammation. © 2022 Wiley Periodicals LLC.