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The oxygen content of the oceans is susceptible to climate change and has declined in recent decades, with the largest effect in oxygen-deficient zones (ODZs), that is, mid-depth ocean regions with oxygen concentrations <5 μmol kg⁻¹ (ref. ). Earth-system-model simulations of climate warming predict that ODZs will expand until at least 2100. The response on timescales of hundreds to thousands of years, however, remains uncertain^{, –}. Here we investigate changes in the response of ocean oxygenation during the warmer-than-present Miocene Climatic Optimum (MCO; 17.0–14.8 million years ago (Ma)). Our planktic foraminifera I/Ca and δ¹⁵N data, palaeoceanographic proxies sensitive to ODZ extent and intensity, indicate that dissolved-oxygen concentrations in the eastern tropical Pacific (ETP) exceeded 100 µmol kg⁻¹ during the MCO. Paired Mg/Ca-derived temperature data suggest that an ODZ …