We have previously reported that the antioxidant curcumin exerts nephroprotection in maleate‐induced renal damage, a model associated with oxidative stress. However, the mechanisms involved in curcumin protective effect were not explored, to assess this issue, curcumin was administered daily by gavage (150 mg/kg) five days before a single maleate (400 mg/kg)‐injection. Curcumin prevented maleate‐induced proteinuria, increased heat shock protein of 72 KDa (Hsp72) expression, and decreased plasma glutathione peroxidase activity. Maleate‐induced oxidative stress by increasing the nicotinamide–adenine dinucleotide phosphate oxidase 4 (NOX4) and mitochondrial complex I‐dependent superoxide anion (O2•—) production, formation of malondialdehyde (MDA)‐ and 3‐nitrotyrosine (3‐NT)‐protein adducts and protein carbonylation and decreased GSH/GSSG ratio. Curcumin treatment ameliorated all the above‐described changes. The maleate‐induced epithelial damage, evaluated by claudin‐2 and occludin expressions, was ameliorated by curcumin. It was found that maleate‐induced oxidative stress promoted mitochondrial fission, evaluated by dynamin‐related protein (Drp) 1 and fission (Fis) 1 expressions and by electron‐microscopy, and autophagy, evaluated by phospho‐threonine 389 from p70 ribosomal protein S6 kinase (p‐Thr 389 p70S6K), beclin 1, microtubule‐associated protein 1A/1B‐light chain 3 phosphatidylethanolamine conjugate (LC3‐II), autophagy‐related gene 5 and 12 (Atg5‐Atg12) complex, p62, and lysosomal‐associated membrane protein (LAMP)‐2 expressions in isolated proximal tubules and by electron‐microscopy and LC‐3 immunolabelling. Curcumin treatment ameliorated these changes. Moreover, curcumin alone induced autophagy in proximal tubules. These data suggest that the nephroprotective effect exerted by curcumin in maleate‐induced renal damage is associated with decreased mitochondrial fission and autophagy. © 2016 BioFactors, 42(6):686–702, 2016