Recurrent mass extinction events (at “biomere”—a biostratigraphic unit—boundaries) characterize the middle Cambrian to Early Ordovician (Tremadocian) time interval that is between the major Cambrian and Ordovician radiations of animal life. A role for anoxia in maintaining elevated extinction rates in the late Cambrian has been proposed based on coincidence of an extinction with positive excursions in δ13Ccarb and δ34SCAS (CAS—carbonate-associated sulfate). Here we examine an Early Ordovician extinction event at the base of the North American Stairsian Stage (upper Tremadocian), and demonstrate concurrent onset of positive excursions in δ13C and δ34S inferred to reflect enhanced organic matter burial under anoxic waters. Sea-level rise may have brought anoxic waters onto the shelf to initiate extinctions. The evidence for δ13C excursions and elevated extinction rates appears to wane in the Tremadocian, consistent with progressive oxygenation of the oceans reaching a threshold that helped facilitate initial stages of the Great Ordovician Biodiversification Event.