Objectives: Decrease of kidney function is frequently observed in the elderly population, and vulnerability and incomplete recovery to acute kidney injury such as ischemic/reperfusion injury (IRI) is considered as one of the mechanisms. It has been suggested the possibility of specific factor mediating the different course of aging kidney. We aimed to investigate the role of nuclear factor erythroid 2-related factor 2 (NRF2), an essential regulator of cellular homeostasis and antioxidant protein, in the recovery of IRI in aging kidney cells. Methods: Primary renal proximal tubule epithelial cells (RPTEC) having undergone long-term culture for cellular senescence were utilized as aged cells. Hypoxia/reoxygenation (H/R) injury was applied with the protocol, which incubated serum-free medium in a hypoxic chamber containing 1% O2 for 24 hours and returned to normoxia for 30 mins. SA-β-galactosidase staining was performed to determine cellular senescence. The expression of NRF2 was depleted using siRNA of NRF2 in RPTEC aged cell under H/R injury. Results: Cell viability was inhibited by H/R in senescent RPTEC and it was exacerbated in NRF2 deficiency. Kidney injury molecule-1 (KIM-1) expression was increased under H/R injury and it was also accentuated with NRF2 deficiency. H/R cellular injury led to increase of reactive oxygen species (ROS) generation and oxidative stress, which caused mitochondrial dysfunction. NRF2 depletion exacerbated ROS production under H/R injury and deteriorated mitochondrial dysfunction through disruption of mitochondrial membrane potential. Conclusions: Our study suggested an important role of NRF2 in the management of oxidative stress and mitochondrial dysfunction of IRI in aging kidney.