The Cenomanian/Turonian boundary (CTB; ~93.9 Ma) is associated with extreme global warmth, increased volcanism, rising global sea level, and the development of Oceanic Anoxic Event 2 (OAE2; ~94 Myr). The examination of the timing and spatial extent of foraminiferal bio-events associated with the event can illuminate the complex interactions between the ocean, climate, and life during this dynamic interval. Although volcanism has been identified as a primary trigger for OAE2, the impetus for its global expansion is less understood. This work integrates planktic and benthic foraminiferal assemblages and geochemical records from multiple localities across the Western Interior Seaway (WIS) to investigate the potential roles of marginal seas and ocean circulation. The WIS was a shallow, epicontinental sea that extended across western North America during the Late Cretaceous. The present investigations records from five distinct WIS localities through OAE2 time intervals to define a paleoceanographic framework. This framework is used to determine the significance of foraminiferal bio-events, compare the timing of bio-events, rising sea level, water mass changes, and volcanism, and test whether the seaway played a role in the development and expansion of the global OAE2. The investigations find evidence for distinct water masses across North-South and East-West transects of the seaway before OAE2. They demonstrate that the WIS is sensitive to sea-level rise and plays a role in ocean circulation as a brief exporter of intermediate waters. The examination of the timing and spatial extent of foraminiferal bio-events provides compelling evidence for a proposed impetus for the global expansion of OAE2. The widespread development of OAE2 was facilitated by gyre circulation through the WIS, triggered by rising sea level. This work demonstrates the role of paleo-marginal seas in circulation through geologic time and especially during perturbations. It also shows the interplay between local, regional, and global impacts of rapid environmental change and the response and recovery of the marine biosphere.