The Cenomanian-Turonian (C-T) interval of the Late Cretaceous was marked by carbon cycle perturbations, eustatic sea level rise, global warming, and ocean anoxic event 2 (OAE2), all of which impacted marine organisms. Cephalopod mollusks, in particular, experienced significant evolutionary radiations and extinctions in the C-T and therefore provide an opportunity to test hypotheses about how marine organisms respond to a warming Earth. How sensitive was cephalopod diversity to these environmental perturbations? In what ways did rates of origination and extinction fluctuate in concert with environmental parameters? Did the geographic distribution of cephalopod species affect their extinction probability? To address these questions, data were examined at two levels of geographic and stratigraphic resolution. A global dataset of 7259 cephalopod species occurrences was compiled at the substage level of temporal resolution, and a subset of these data representing 4975 species occurrences within the North American Western Interior Seaway and Gulf Coastal Plain (WIS) were further resolved to the ammonoid biozone level. These data were used to determine species diversity, origination and extinction rates, and geographic ranges and distributions throughout the C-T interval. Globally, cephalopod species diversity dropped only slightly across the C/T boundary but turnover was significant, with 82% of Late Cenomanian species dying out at or before the C/T. Turnover was even higher at the Early/Middle Turonian boundary. Using a finer stratigraphic resolution reveals that, within North America, diversity drops occurred in association with carbon isotopic excursions throughout the C-T. Zone-level origination rates remained high throughout most of OAE2 while extinctions occurred in two pulses at the end of the E. septemseriatum and N. juddii biozones, reflecting the early development of OAE2 and an increase in runoff to the WIS, respectively. Diversity in the WIS rebounded quickly in the early Turonian while OAE2 was still ongoing. While globally species with larger geographic ranges were more likely to survive the C/T extinction as well as other C-T turnover events, no such relationship was seen for cephalopods within the WIS, reflecting regional variations in the biotic response to environmental change.