AbstractClimate change is expected to increase the strength of ocean Oxygen Deficient Zones (ODZs), but we lack a detailed understanding of the temporal or spatial variability of these ODZs. A 50‐year time series in the Eastern Tropical North Pacific (ETNP) ODZ revealed that it has strengthened by 30% from 1994 to 2019. We subdivided the ODZ into a core and a deep layer based on potential density and revealed that different processes control the magnitude of fixed nitrogen loss between these regions. We postulate that the depth of the upper ETNP ODZ water mass, the 13°C Water, influences the organic carbon supply to the core ODZ and therefore its strength. We correlated the maximum fixed nitrogen loss in the core ODZ with a nearby sedimentary nitrogen isotope record and found that this recent increase in the magnitude of fixed nitrogen loss occurred only a few times over the last 1,200 years. Using this correlation, we derived the first confidence interval for the natural variability of the maximum fixed nitrogen loss within the ETNP ODZ, which has a range of 3.3 μmol kg−1 (p = 0.01). While the current increase is only comparable to two previous events, it is within the confidence interval for natural variability (p = 0.03). The deep ODZ also strengthened from 2016 to 2019 by approximately 30%, but this increase occurred more rapidly than the core ODZ, and this dramatic increase was not observed over the rest of the 40 years. Climate‐driven intensification could lead to unprecedented changes in the ETNP ODZ within the next decade.