The impact of global climate events on local ecosystems can vary spatially. Understanding this potential heterogeneity can illuminate which environments will be most impacted and the proximal drivers of ecosystem responses. Cenomanian–Turonian marine deposits of the Western Interior Seaway (WIS) record paleoceanographic changes associated with the Greenhorn transgression and the onset of Oceanic Anoxic Event 2 (OAE2). They provide an ideal setting to study basin-wide paleoecological responses during a global perturbation. Here, we integrate benthic foraminiferal assemblages from before, during, and after OAE2 via multivariate ordination analysis to examine spatial patterns in faunal responses across the western United States on a common scale and to interrogate a previously defined faunal marker commonly used for basin-wide correlation, the Benthonic Zone (BZ). We identify oxygenation and organic matter quality as primary and secondary controls of faunal variation across the 10 stratigraphic records and use this variation to infer paleoenvironmental changes. Stratigraphic trends reveal, in contrast to previous studies, deoxygenation at the onset of OAE2. They also reveal temporal patterns in oxygenation and productivity consistent with the gradual northward migration of a southern water mass into the WIS. This spatial heterogeneity hinders the use of the BZ as a temporal marker, because assemblages change in response to diachronous environmental change, and thus timing of the BZ with respect to OAE2 is not consistent across the basin. Our study demonstrates that regional processes can overshadow ecosystem responses to global events and underscores the importance of considering how changes in the position of water masses impact the expression of global biogeochemical perturbations.