The late Silurian Lau/Kozlowskii bioevent marks a time interval with substantial loss in marine biodiversity linked to the largest positive carbon isotope excursion (Mid-Ludfordian CIE; MLCIE) recorded in the Phanerozoic (δ¹³C_carb peaks at +8–10‰). The positive δ¹³C excursion and the extinctions have been linked to increased marine productivity (ocean eutrophication), leading to increased organic carbon burial, and expansion of marine anoxia in shallow continental seas. To explore this idea, we reconstruct the contemporaneous global extent of marine anoxia using uranium (U) isotopes from Ludfordian marine carbonates sampled from two widely spaced paleogeographic locations. Our δ²³⁸U results demonstrate that the overall MLCIE was not coupled to expanding marine anoxia and a presumed associated increased marine primary productivity. Instead, a time interval of widespread global anoxia occurred only before and during the onset of the MLCIE (up to end of P. siluricus conodont zone; ca. δ¹³C ∼ 2.6‰), which is when the extinctions took place. Strong climatic variability at this time suggests anoxia and climate change led to the extinctions of the Lau/Kozlowskii bioevent. The major part of the rise to the peak (δ¹³C ∼ 10‰) and falling limb of the MLCIE was not coupled with corresponding changes in δ²³⁸U values. Thus, increased marine primary productivity and marine anoxia may have caused the initial carbon cycle disturbance and the extinctions but was not a main driver for the continued growth and exceptional magnitude of the MLCIE.