The ocean enabled the diversification of life on Earth by adding O₂ to the atmosphere, yet marine species remain most subject to O₂ limitation. Human industrialization is intensifying the aerobic challenges to marine ecosystems by depleting the ocean's O₂ inventory through the global addition of heat and local addition of nutrients. Historical observations reveal an ∼2% decline in upper-ocean O₂ and accelerating reports of coastal mass mortality events. The dynamic balance of O₂ supply and demand provides a unifying framework for understanding these phenomena across scales from the global ocean to individual organisms. Using this framework, we synthesize recent advances in forecasting O₂ loss and its impacts on marine biogeography, biodiversity, and biogeochemistry. We also highlight three outstanding uncertainties: how long-term global climate change intensifies ocean weather events in which simultaneous heat and hypoxia create metabolic storms, how differential species O₂ sensitivities alter the structure of ecological communities, and how global O₂ loss intersects with coastal eutrophication. Projecting these interacting impacts on future marine ecosystems requires integration of climate dynamics, biogeochemistry, physiology, and ecology, evaluated with an eye on Earth history. Reducing global and local impacts of warming and O₂ loss will be essential if humankind is to preserve the health and biodiversity of the future ocean.