The Pacific hosts the largest oxygen minimum zones (OMZs) in the world ocean, which are thought to intensify and expand under future climate change, with significant consequences for marine ecosystems, biogeochemical cycles, and fisheries. At present, no deep ventilation occurs in the North Pacific due to a persistent halocline, but relatively better-oxygenated subsurface North Pacific Intermediate Water (NPIW) mitigates OMZ development in lower latitudes. Over the past decades, instrumental data show decreasing oxygenation in NPIW; however, long-term variations in middepth ventilation are potentially large, obscuring anthropogenic influences against millennial-scale natural background shifts. Here, we use paleoceanographic proxy evidence from the Okhotsk Sea, the foremost North Pacific ventilation region, to show that its modern oxygenated pattern is a relatively recent feature, with little to no ventilation before six thousand years ago, constituting an apparent Early–Middle Holocene (EMH) threshold or “tipping point.” Complementary paleomodeling results likewise indicate a warmer, saltier EMH NPIW, different from its modern conditions. During the EMH, the Okhotsk Sea switched from a modern oxygenation source to a sink, through a combination of sea ice loss, higher water temperatures, and remineralization rates, inhibiting ventilation. We estimate a strongly decreased EMH NPIW oxygenation of ∼30 to 50%, and increased middepth Pacific nutrient concentrations and carbon storage. Our results (i) imply that under past or future warmer-than-present conditions, oceanic biogeochemical feedback mechanisms may change or even switch direction, and (ii) provide constraints on the high-latitude North Pacific’s influence on mesopelagic ventilation dynamics, with consequences for large oceanic regions.