Although ginseng (Panax ginseng C.A. Meyer) has received extensive attention in the treatment and prevention of type 2 diabetes mellitus (T2DM) in the past few decades, there are few studies on the complications of T2DM. At present, obesity-linked diabetic nephropathy (DN) has become the most prevailing element of the end-stage renal failure in the world. The aim of this work is to evaluate the ameliorative effects of ginsenoside Rh1 (G-Rh1) on DN induced by high fat diet plus streptozotocin (HFD/STZ) through some potential and combined mechanisms of action. The results showed that G-Rh1 treatment at 5 and 10 mg/kg for 8 weeks exerted excellent effects in controlling fasting blood glucose (FBG), improving glucose tolerance, and increasing insulin level. In addition, G-Rh1 effectively prevents the excessive production of advanced glycation end products (AGEs), a diabetic nephropathy marker, in HFD/STZ induced DN mice. Meanwhile, oxidation indicators including SOD, GSH, and MDA were improved by G-Rh1 treatment to varying degrees. It is worth noting that G-Rh1 not only inhibits the secretion of Nox1 and Nox4 in kidney tissues, but also has an inhibitory effect on inflammatory factors and NF-κB signaling pathway. Importantly, further in-depth research on molecular mechanisms provides vital evidence that the ameliorative effect of G-Rh1 on DN is related to the inhibition of apoptosis and the AMPK/PI3K/Akt signaling pathway. In summary, G-Rh1 may be of great value in improving the treatment of DN although more experimental data is needed.