The Paleocene–Eocene Thermal Maximum (PETM) is associated with climatic change and biological turnover. It shares features with the Oceanic Anoxic Events (OAEs) of the Mesozoic, such as transient global warming and biogeochemical perturbations. However, the PETM experienced a more muted expansion of marine anoxia compared to the Mesozoic OAEs (especially OAE 2), with benthic deoxygenation being geographically restricted and limited evidence for photic zone euxinia. We explore the extent and drivers of marine deoxygenation during the PETM using biomarkers for water column euxinia and anoxia and data-constrained biogeochemical climate model (cGENIE) simulations. These reveal that the water column in the North-East Peri-Tethys became anoxic during the PETM, with euxinic conditions reaching the photic zone. Our simulations show that this developed due to a global increase in the ocean nutrient inventory, similar to findings for OAE 2. The particularly strong regional response in the NE Peri-Tethys appears to arise from a combination of global forcing and regionally restricted circulation. Unlike OAE 2, anoxia and PZE do not become widespread in our PETM simulations, consistent with geochemical and biological indicators. This globally muted response could result from a reduced oceanic phosphate inventory prior to the PETM and/or a smaller increase during it relative to the mid-Cretaceous ocean. Our observations suggest that similar feedback mechanisms operated in response to disparate Cenozoic (PETM) and Mesozoic (OAEs) transient global warming events, while also highlighting that background conditions such as geography and nutrient status are crucial in modulating the sensitivity of Earth’s system to them.