Ongoing global warming could persist far into the future, because natural processes require decades to hundreds of thousands of years to remove carbon dioxide from fossil-fuel burning from the atmosphere1,2,3. Future warming may have large global impacts including ocean oxygen depletion and associated adverse effects on marine life, such as more frequent mortality events4,5,6,7,8, but long, comprehensive simulations of these impacts are currently not available. Here we project global change over the next 100,000 years using a low-resolution Earth system model9, and find severe, long-term ocean oxygen depletion, as well as a great expansion of ocean oxygen-minimum zones for scenarios with high emissions or high climate sensitivity. We find that climate feedbacks within the Earth system amplify the strength and duration of global warming, ocean heating and oxygen depletion. Decreased oxygen solubility from surface-layer warming accounts for most of the enhanced oxygen depletion in the upper 500 m of the ocean. Possible weakening of ocean overturning and convection lead to further oxygen depletion, also in the deep ocean. We conclude that substantial reductions in fossil-fuel use over the next few generations are needed if extensive ocean oxygen depletion for thousands of years is to be avoided.