Ischemia-reperfusion (I-R) injury is involved in the pathogenesis of several human diseases. In the present study, the kinetics of the HS producing enzymes-nuclear factor erythroid 2-like 2 (Nrf2)-antioxidant proteins axis under anoxia or reoxygenation was evaluated, as well as its effects on survival of mouse renal proximal tubular epithelial cells (RPTECs). In RPTECs subjected to anoxia and subsequent reoxygenation, reactive oxygen species (ROS) production, lipid peroxidation, ferroptotic cell death, the levels of the HS producing enzymes and HS, the expression of Nrf2 and its transcriptional targets superoxide dismutase-3, glutathione reductase, ferritin H and cystine-glutamate antiporter, as well as apoptosis, and the levels of p53, Bax and phosphorylated p53 were assessed. When needed, the HS producing enzyme inhibitor aminooxyacetate, or the ferroptosis inhibitor α-tocopherol, were used. Reoxygenation induced ferroptosis, whereas anoxia activated the p53-Bax pathway and induced apoptosis. The HS producing enzymes-Nrf2-antioxidant proteins axis was activated only during anoxia and not during reoxygenation, when cellular viability is threatened by ROS overproduction and the ensuing ferroptosis. The activation of the above axis during anoxia ameliorated the effects of the apoptotic p53-Bax pathway, but did not adequately protect against apoptosis. In conclusion, the HS-Nrf2 axis is activated by anoxia, and although it reduces apoptosis, it does not completely prevent apoptotic cell death. Additionally, following reoxygenation, the above axis was not activated. This mistimed activation of the HS producing enzymes-Nrf2-antioxidant proteins axis contributes to reoxygenation-induced cell death. Determining the exact molecular mechanisms involved in reoxygenation-induced cell death may assist in the development of clinically relevant interventions for preventing I-R injury.