The Cenomanian to Turonian boundary transition (ca. 95–93 Ma) represents one of the most profound global perturbations in the carbon cycle of the past 140 m.y. This interval is characterized by widespread deposition of organic-rich fine-grained sediment marked by a globally recognized positive carbon isotope excursion (CIE) reflecting the widespread removal of 12C-enriched organic matter in marine sediments under global anoxic greenhouse conditions. However, the exact timing and trigger of this inferred global phenomenon, termed Oceanic Anoxic Event 2 (OAE-2), is still debated, with recent studies showing diachroneity between the deposition of the organic-rich sediment and the CIE, and conflicting interpretations on detailed redox analyses in several of these inferred anoxic settings. Here we present the first evidence for widespread and persistent oxygenation during OAE-2 based primarily on the distribution of redox-sensitive trace metals and biota preserved in sedimentary rocks from the Western Interior Seaway of North America. Our data indicate anoxic-euxinic conditions in the mid- to late Cenomanian, but improved bottom-water oxygenation prior to and during the CIE. Trace metal enrichments support large volumes of mafic volcanism possibly from the High Arctic large igneous province (HALIP), which occur within the middle of the CIE indicating that the emplacement of LIPs was not the primary trigger of the Cenomanian-Turonian CIE. The apparent paradox of an oxygenated phase within OAE-2 suggests a much more complex carbon cycle during these global perturbations than previously thought. These findings have important implications for greenhouse carbon cycle changes over time scales of 0.1–10 m.y.