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Diabetic nephropathy (DN) is one of the causes of end-stage renal failure, featuring renal fibrosis. However, autophagy, a vital process for intracellular homeostasis, can counteract renal fibrosis. Moreover, NAD(P)H: quinone dehydrogenase 1 (NQO1) modulates the ratios of reduced/oxidized nicotinamide nucleotides, exerting a cytoprotective function. Here, to examine the role of <i>NQO1</i> genes in DN progression, the levels of autophagy-related proteins and pro-fibrotic markers were assessed in silencing or overexpression of <i>NQO1</i> in human proximal tubular cells (HK2), and C57BL/6 (wild-type) and <i>Nqo1 knockout</i> (KO) mice injected to streptozotocin (50 mg/kg). NQO1 deficiency impaired the autophagy process by suppressing basal expression of ClassⅢ PI 3-kinase (Vps34) and autophagy-related (ATG)14L and inducing the expressions of transforming growth factor beta (TGF-β1), Smad3, and matrix metallopeptidase9 (MMP9) in high-glucose (HG) -treated HK2 cells. Meanwhile, <i>NQO1</i> overexpression increased the expression of Vps34 and ATG14L, while, reducing TGF-β1, Smad3 and MMP9 expression. <i>In vivo</i>, the expression of Vps34 and ATG14L were suppressed in <i>Nqo1</i> KO mice indicating aggravated glomerular changes and interstitial fibrosis. Therefore, <i>NQO1</i> deficiency dysregulated autophagy initiation in HK2 cells, with consequent worsened renal cell damage under HG condition. Moreover, STZ-treated <i>Nqo1</i> KO mice showed that <i>NQO1</i> deficiency aggravated renal fibrosis by dysregulating autophagy.