Hyperuricemia (HUA)-induced oxidative stress is a crucial contributor to hyperuricemic nephropathy (HN), but the molecular mechanisms underlying the disturbed redox homeostasis in kidneys remain elusive. Using RNA sequencing, together with biochemical analyses, we found that nuclear factor erythroid 2-related factor 2 (NRF2) expression and nuclear localization levels were increased in early HN progression and then gradually declined below the baseline level. We identified the impaired activity of the NRF2-activated antioxidant pathway as a driver of oxidative damage in HN progression. Through deletion, we further confirmed aggravated kidney damage in knockout HN mice compared with HN mice. In contrast, the pharmacological agonist of NRF2 improved kidney function and alleviated renal fibrosis in mice. Mechanistically, the activation of NRF2 signaling reduced oxidative stress by restoring mitochondrial homeostasis and reducing NADPH oxidase 4 (NOX4) expression in vivo or in vitro. Moreover, the activation of NRF2 promoted the expression levels of heme oxygenase 1 (HO-1) and quinone oxidoreductase 1 (NQO1) and enhanced the antioxidant capacity of cells. Furthermore, the activation of NRF2 ameliorated renal fibrosis in HN mice through the downregulation of the transforming growth factor-beta 1 (TGF-β1) signaling pathway and ultimately delayed the progression of HN. Collectively, these results suggested NRF2 as a key regulator in improving mitochondrial homeostasis and fibrosis in renal tubular cells by reducing oxidative stress, upregulating the antioxidant signaling pathway, and downregulating the TGF-β1 signaling pathway. The activation of NRF2 represents a promising strategy to restore redox homeostasis and combat HN.