New carbon and oxygen isotope data from carbonates spanning the Frasnian–Famennian (F–F) boundary in the Guilin area, South China, show a broad positive δ13C rise and fall, with sharp, short-lived negative δ13C events; this pattern is comparable to that in Europe and North America. The integration of the isotope stratigraphy with high-resolution sequence stratigraphy corroborates the onset of the positive δ13C excursion during a third-order sea-level fall in the latest Frasnian. This can best be explained through increased burial of Corg during the sea-level fall, brought about by increased organic productivity caused by increased continent-derived nutrient flux to the ocean due to enhanced weathering through the proliferation of land plants in the Devonian. This scenario would have resulted in anoxic and eutrophic conditions over epicontinental seas and blooms of cyanobacteria, creating a highly stressful and fragile ecosystem for oligotrophic normal-marine benthic organisms and leading to their massive decline. The global third-order sea-level fall near the end of the Frasnian may have led to gas hydrate dissociation (giving the negative δ13C events), and caused wild climatic fluctuations. The subsequent short-term events of sea-level rise, anoxia and eutrophication in the latest part of the F–F transition would have placed additional environmental stresses on the already weakened biota, leading to their further demise.