The Cenomanian-Turonian period recorded one of the largest disruptions to the oxygen and carbon cycles, the Oceanic Anoxic Event 2 (OAE2, 94 Ma). This event is global, yet paleo-reconstructions document heterogeneous ocean oxygenation states and sedimentary carbon contents, both temporally and spatially, suggesting that several mechanisms are at play. To better understand the long-term controls on oceanic oxygen and the initial oxygenation conditions prevailing at the beginning of OAE2, we perform numerical simulations of the Cenomanian using the IPSCL-CM5A2 Earth System Model, which includes a marine biogeochemistry component. We examine the control of the biogeochemical states of the global and Central Atlantic oceans by the depth of the Central American Seaway (CAS). The simulations show that a vigorous ocean circulation existed during the Cenomanian and that dysoxia/anoxia was caused by paleogeography rather than by ocean stagnation. The existence of restricted basins, disconnected from the deep global circulation and supplied with oxygen-depleted waters from Oxygen Minimum Zones of the surrounding basins, played a key role in the development of dysoxic/anoxic regions. A comparison with redox-proxy data suggests that a deep connection existed between the Pacific and Central Atlantic prior to OAE2. A shallowing of the CAS may have contributed to the establishment of enhanced anoxia in the Central Atlantic during OAE2. The paleogeographic configuration and that of gateways and submarine topographic barriers appear as major long-term controllers of the oceanic circulation and oxygen distribution, leading to low-oxygen concentrations in extended parts of the ocean as prerequisite conditions for OAEs to occur.