N-acetyl cysteine prevents synergistic, severe toxicity from two hits of oxidative stress.

•A severe stress model of neurodegeneration was established with dual H2O2 hits.•Three independent viability assays confirmed severe, synergistic cell loss.•Catalase defenses were raised by the first hit.•Glutathione defenses were reduced by the first and second hit.•N-acetyl cysteine prevented glutathione loss and robustly protected against severe H2O2 toxicity.