The Late Cenomanian Plenus Cold Event is one of the most enigmatic paleoclimate episodes in Earth history with potential to inform understanding of global climate system variability under greenhouse warming conditions, as well as internal feedback pathways that modulate such variability. Following an interpreted massive addition of volcanic CO2 to the atmosphere and warming that led to a major ocean anoxic event (OAE2), there was a brief interval of cooling recorded in oxygen isotopes and biogeographic data. Here we present evidence that cooling was absent or muted within the Western Interior Seaway (WIS). Clumped isotope data from the basin suggest persistent extreme warmth during the Late Cenomanian, macroinvertebrate fossil assemblages do not record a decrease in temperature, and changes in other paleoceanographic proxies do not correlate temporally with Plenus interval signals from other locales. Using select proxy data to guide construction of GCM model simulations, we explore possible hypotheses to explain these observations. Our results suggest that the paleogeographic configuration of the basin and its gateways to adjoining oceans, which evolved in association with changing pCO2 and sea level, influenced winter sea ice formation at the northern aperture of the seaway, water mass circulation, salinity, temperature, and water column stratification. We propose that northward advection of warm Tethyan water muted expression of Plenus cooling in the seaway. Understanding the unique character of the Western Interior paleoceanographic record provides critical input for the development of robust models of ancient Earth System dynamics and should aid predictions of future climate system dynamics.