We studied how changes in Earth’s orbit affected ocean oxygen during the Devonian, a time of repeated environmental crises and extinctions. Using computer simulations, we show that certain orbital cycles, especially eccentricity maxima, exacerbate oxygen loss in the oceans, while obliquity also played a key role at high latitudes. The results also help explain why records from different places show contrasting signals and provide new insight into how natural climate cycles can affect ocean life.