PARP inhibitors (PARPi) are clinically effective in homologous recombination (HR)-deficient tumours, but their application in HR-proficient cancers remains limited. Although hypoxia suppresses HR, this repression alone does not adequately sensitise cancer cells to PARPi due to insufficient endogenous DNA damage. We hypothesised that introducing a hypoxia-selective source of DNA damage could enhance PARPi efficacy. Here, we show that the hypoxia-activated prodrug tirapazamine (TPZ) synergises with the PARPi talazoparib to induce cytotoxicity in HR-proficient non-small cell lung cancer (NSCLC) cells, with preferential activity under hypoxia. Mechanistically, this synergy is driven by increased DNA double-strand breaks (DSBs) and replication stress. These lesions are largely resolved in normoxia but persist in hypoxia. In hypoxic spheroids derived from HR-proficient NSCLC cell lines, the TPZ and talazoparib combination significantly inhibited spheroid growth. In subcutaneous xenografts, the combination similarly suppressed tumour growth in the highly hypoxic A549 and CORL105 models, while showing minimal efficacy in the less hypoxic Calu-3 and H3122 tumours. This study highlights the potential of hypoxia-targeted DNA-damaging agents to expand PARPi utility to HR-proficient cancers and demonstrates that hypoxia enhances the therapeutic effect of this combination.