This study investigated if the nephroprotective effect of Salidroside T1DM rats involves activation of AMPK/SIRT1. Rats were divided into control or T1DM and treated with vehicle or Salidroside (100 mg/kg) for 56 days. Mesangial cells were cultured in LG or HG media with or without Salidroside (100 µM/L) for 24 hr. Also, HG + Salidroside-treated cells were pre-incubated with EX-527 or compound C (CC) for 1 hr. With reducing glucose levels, Salidroside improved kidney structure/function in the T1DM rat. It also increased GSH and Bcl-2 levels in control and T1DM rats and inhibited ROS, increased activation of AMPK and nuclear SIRT1, and lowered acetylation of P53 and FOXO-1 in control and T1DM rats and in LG and HG-treated cells. These effects were abolished by EX-527 and CC. Also, CC decreased the nuclear levels of SIRT1. In conclusion, Salidroside attenuates DN in T1DM rats by activation of AMPK and subsequently, SIRT1. PRACTICAL APPLICATIONS: This animal and pre-clinical study shows that Salidroside is able to ameliorate DN in T1DM-induced rats and showed that it mainly acts by a hypoglycemic effect and activation of renal AMPK/SIRT1 axis. Given the wide tissue stimulatory effect of AMPK on peripheral glucose utilization, lipogenesis, and other cell signaling pathways, these data are encouraging to investigate the anti-diabetic effect of glycoside in more clinical trials.