The emplacement of a Large Igneous Province (LIP) is implicated in the triggering of the Cenomanian-Turonian Oceanic Anoxic Event 2 (OAE 2). Evidence for a similar initiation mechanism for the mid-Cenomanian Event (MCE) is unclear. In this study, a reconstruction of mid-Cenomanian seawater 187Os/188Os, the first for the Western Interior Seaway, tests the competing roles of LIP versus continental weathering activity in triggering the MCE. The absence of a prolonged unradiogenic Os isotope excursion (low 187Os/188Os) at the onset of the MCE interval argues against LIP involvement in the event’s initiation. Rather, more radiogenic 187Os/188Os at the onset, that continues to rise to the middle of the MCE, indicates that the event was triggered by increased continental weathering. The combination of decreasing 187Os/188Os from the middle of the MCE onward, coincident with a 40Ar/39Ar age of 96.4 Ma of basalts from Ellesmere Island, Canada, is consistent with High Arctic LIP-related volcanic activity that may have contributed to the end of the MCE. These new data on the MCE thus indicate that LIP activity is not always the trigger for carbon cycle perturbation and associated climate change.