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Anaerobic microbial activity in the ocean causes losses of bioavailable nitrogen and emission of nitrous oxide to the atmosphere, but its predictability at global scales remains limited. Resource ratio theory suggests that anaerobic activity becomes sustainable when the ratio of oxygen to organic matter supply is below the ratio required by aerobic metabolisms. Here, we demonstrate the relevance of this framework at the global scale using three‐dimensional ocean datasets, providing a new interpretation of existing observations. Evaluations of the location and extent of anoxic zones and a diagnostic rate of pelagic nitrogen loss are consistent with previous estimates. However, we demonstrate that a threshold based on substrate‐supply fluxes is qualitatively different from a threshold based solely on the ambient oxygen concentration. This implies that use of the flux‐based threshold in global biogeochemical models can result in different predictions of anaerobic activity and nitrogen loss. Plain Language Summary: Where oxygen concentrations are sufficiently low in the ocean, nutrients are lost to the atmosphere because of specialized activity by microorganisms. Typically, biogeochemical models prescribe a critical oxygen concentration as a threshold to predict this activity. Here, we explain and demonstrate that an alternative threshold is more appropriate. The new threshold takes into account the supply flux of oxygen, rather than the concentration, as well as the supply flux of organic matter that is consumed by the microorganisms. We use global datasets to demonstrate that this threshold is relevant at the global scale. Since it is distinct from and more mechanistic than the typical oxygen concentration threshold, it may be used in global biogeochemical climate models to improve their ability to predict the loss of nutrients to the atmosphere and the impact on the climate system. Key Points: We show that a threshold for anaerobic activity based on oxygen and organic matter fluxes is consistent with global ocean observationsOur diagnostic calculation uses global datasets to define the three major pelagic anoxic zones in a new wayThe flux‐based threshold is qualitatively different than a threshold based on the oxygen concentration [ABSTRACT FROM AUTHOR]