This study investigated the nephroprotective role of acylated ghrelin (AG) against DOX‐induced nephropathy and examined whether the protection involves silent information regulator 1 (SIRT1). Rats were divided into control, control + AG, DOX, DOX + AG, DOX + AG + [D‐Lys3]‐GHRP‐6 (a ghrelin receptor antagonist), and DOX + AG + EX‐527 (a sirt1 inhibitor). DOX was given over the first 2 weeks. AG (10 ng/kg) and both inhibitors were given as 3 doses/wk for 5 weeks. AG improved the structure and the function of the kidneys; down‐regulated the renal expression of TGF‐β1, collagen 1A1 and α‐SMA; and inhibited the renal collagen deposition in the kidneys of DOX‐treated rats. Concomitantly, it reduced the renal levels of ROS, MDA, TNF‐α, and IL‐6 and protein levels of cytochrome‐c, TGF‐β1, Smad3 and α‐SMA in these rats. In both the control and DOX‐treated rats, AG significantly increased the renal levels of SOD and GSH, decreased the expression of cleaved caspase‐3 and Bax, increased the total levels and the nuclear activity of SIRT1 and reduced the deacetylation of p53, NF‐κB and FOXO‐31. All the effects were abolished by the concurrent administration of EX‐527 and [D‐Lys3]‐GHRP‐6. In conclusion, AG prevents DOX‐induced nephropathy in SIRT1 and GSHRa1‐dependent mechanism.