Future climate change is predicted to significantly impact ocean circulation and, potentially, to reduce ocean oxygenation. Paradoxically, the transition from the warm Pliocene, often held as an analog for a future, warmer Earth, to the cool Pleistocene appears to accompany a decrease in intermediate water oxygenation. The Plio-Pleistocene cooling begins with the onset of major Northern Hemisphere glaciation, around 3.0-2.7 million years ago (Ma). High latitude cooling and extension of the polar ice caps led to cooling of the deep ocean and shoaling of the thermocline. The transition culminated in the cooling of the whole surface ocean and establishment of strong zonal and meridional atmospheric circulation from 2.0 Ma. A compilation of high-resolution nitrogen isotope records from the eastern equatorial Pacific, North Pacific, and the Arabian Sea and a global multi-site survey, indicates that regional intensification of oxygen minimum zones (OMZs) and expansion of water column denitrification accompanied the cooling and circulation changes at ~2.0 Ma. Large-scale open ocean suboxia intensified with the inception of a modern polar frontal system, despite lower temperatures and thus higher initial oxygen contents of the mode waters themselves. This likely reflects the increased importance of aged mode waters as the principle conduit of nutrients and oxygen to the OMZs. These results stress how climate-related changes in circulation may complicate our ability to predict ocean biogeochemical changes on a changing Earth.