The middle Paleozoic (∼420-350 Myr) records a major increase in ocean-atmosphere oxygen levels; however, the timing and pattern of oxygenation are poorly constrained. Two well-dated North American locations in Nevada and Illinois were used to generate a high-resolution U-isotopic profile (δ 238 U) spanning ∼70 Myr of the middle Paleozoic. Stratigraphic and geochemical data support the interpretation that the Nevada profile represents a near-primary record of global-ocean redox variations. First-order δ 238 U trends indicate strongly reducing oceans during the late Silurian and Early Devonian, terminated by a major oxygenation event near the Emsian-Eifelian boundary (∼395 Ma). More oxic seawater conditions persisted for the next 30+ Myr, but were punctuated by multiple Myr-scale anoxic events during the Middle-Late Devonian and Early Mississippian that correlate with known global biotic crises, positive δ 13 C excursions, and widespread organic-rich facies deposition. The timing of the ∼395 Ma oxygenation event suggests that the O 2 rise was the result of increased photosynthesis and organic carbon burial linked to diversification of late Silurian to earliest Middle Devonian terrestrial plants, rather than to subsequent Devonian increases in terrestrial plant root depth, tree height, lignin content, or seed reproduction. These findings demonstrate that early colonization of continents by relatively small, shallowly rooted plants with geographically limited ranges was sufficient to drive long-term oxygenation of the ocean-atmosphere system, paving the way for the evolution of large, mobile animals that have dominated the Earth's surface since the middle Paleozoic.