Abstract Ischemic acute kidney injury (iAKI) in diabetes mellitus is associated with a rapid deterioration of kidney function, more than in non-diabetic subjects. TVP1022, non-MAO inhibitor S-isomer of rasagiline, possesses anti-oxidative and anti-apoptotic activities. The current study examines the effects of TVP1022 and Tempol, on iAKI in diabetic rats. Diabetes was induced by Streptozotocin. iAKI was induced by clamping left renal artery for 30 min, in both diabetic and non-diabetic rats. Right intact kidney served as control. 48 h following ischemia, urinary flow (V), sodium excretion (UNaV) and glomerular filtration rate (GFR) in both ischemic and non-ischemic kidneys were determined. The nephroprotective effects of tempol and TVP1022 were examined in these rats. Hematoxylin and eosin staining, 4HNE immunofluorescent and nitrotyrosine immunohistochemistry were performed on renal tissues of the various experimental groups. Compared with normoglycemic rats, iAKI in diabetic animals caused more profound reductions in V, UNaV, and GFR. Tempol and TVP1022 treatment increased GFR by two and four fold in diabetic ischemic kidney, respectively. Besides hemodynamic perturbations, iAKI markedly increased renal immunoreactive 4HNE and nitrotyrosin staining in both diabetic and non-diabetic rats. Moreover, iAKI increased medullary necrosis, congestion and casts. Noteworthy, these increases were to a larger extent in ischemic diabetic kidney. TVP1022, and to a lesser extent Tempol, decreased nitrotyrosin and 4HNE immunoreactivities, and necrosis and casts formation in the renal medulla. TVP1022 treatment improves renal dysfunction and histological changes in iAKI diabetic model, suggests a role for TVP1022 therapy in kidney injury.