Lake ecosystems are increasingly affected by climate warming, which alters water temperature and seasonal layering, with consequences for water quality and ecosystem functioning. Oxygen in deeper waters is essential for aquatic life and nutrient cycling, but may decline as warming strengthens stratification, reducing vertical mixing while biological activity continues to consume oxygen. Here, we apply a numerical model of oxygen depletion, driven by thermal dynamics from an ensemble of three lake and five climate models, to project deep-water oxygen changes in 73 globally distributed lakes from 2015 to 2099. Under a high-end climate change scenario, oxygen depletion is projected to become more frequent and prolonged, particularly in nutrient-rich lakes, where many are expected to experience extended oxygen-free conditions. Less nutrient-rich lakes show smaller but increasing oxygen declines. These results suggest that nutrient reductions could help sustain oxygen conditions, although continued warming is likely to increase ecological stress.