The Ordovician (Hirnantian; 445 Ma) hosts the second most severe mass extinction in Earth history, coinciding with Gondwanan glaciation and a growing body of geochemical evidence for marine anoxia. It remains unclear whether global cooling, expanded oxygen-deficiency, or a combination drove the Late Ordovician Mass Extinction (LOME). Here, we present new paired iodine and sulfur isotope geochemical data from three globally distributed carbonate successions to constrain changes in local and global marine redox conditions. Iodine records suggest locally anoxic conditions were potentially pervasive on shallow carbonate shelves, while sulfur isotopes suggest a reduction in global euxinic (anoxic and sulfidic) conditions. Late Katian sulfate-sulfur isotope data show a large negative excursion that initiated during elevated sea level and continued through peak Hirnantian glaciation. Geochemical box modeling suggests a combination of decreasing pyrite burial and increasing weathering are required to drive the observed negative excursion. This reduction of pyrite burial suggests a ~3% decrease of global seafloor euxinia during the Late Ordovician. The sulfur datasets spanning the late Hirnantian–early Silurian provide further evidence that this trend was followed by increases in euxinia which coincided with eustatic sea-level rise during subsequent deglaciation. A persistence of shelf anoxia against a backdrop of waning then waxing global euxinia was linked to the two LOME pulses. These results place important constraints on both local and global marine redox conditions throughout the Late Ordovician and suggest that non-sulfidic shelfal anoxia—along with glacioeustatic sea level and climatic cooling—were important factors leading to the LOME.