Ocean deoxygenation has been observed in all major ocean basins over the past 50 yr. Although this signal is largely consistent with oxygen changes expected from anthropogenic climate change, the contribution of external forcing to recent deoxygenation trends relative to natural internal variability is yet to be established. Here we conduct a formal optimal fingerprinting analysis to investigate if external forcing has had a detectable influence on observed dissolved oxygen concentration ([O2]) changes between ∼1970 and ∼1992 using simulations from two Earth System Models (MPI-ESM-LR and HadGEM2-ES). We detect a response to external forcing at a 90% confidence level and find that observed [O2] changes are inconsistent with internal variability as simulated by models. This result is robust in the global ocean for depth-averaged (1-D) zonal mean patterns of [O2] change in both models. Further analysis with the MPI-ESM-LR model shows similar positive detection results for depth-resolved (2-D) zonal mean [O2] changes globally and for the Pacific Ocean individually. Observed oxygen changes in the Atlantic Ocean are indistinguishable from natural internal variability. Simulations from both models consistently underestimate the amplitude of historical [O2] changes in response to external forcing, suggesting that model projections for future ocean deoxygenation may also be underestimated.