The present study reviews the main geochemical, sedimentological, and paleontological events associated with one of the largest perturbations in the Phanerozoic carbon cycle, the Mid-Ludfordian Carbon Isotope Excursion (MLCIE), which is globally documented in late Silurian marine successions. Climate changes associated with the MLCIE are not yet well documented in contrast to most other Silurian CIEs. We report seawater surface temperature changes across the entire MLCIE using delta O-18(apatite) records of conodonts originating from different regions located in temperate as well as tropical paleolatitudes. Significant positive delta O-18(apatite) excursions (up to 3.8 parts per thousand) measured in temperate-water areas of the Prague Basin and Carnic Alps (peri-Gondwana) as well as in the tropical areas of Baltica (Laurussia) and Australia (Gondwana) provide evidence for significant global cooling during the MLCIE. The marked cooling of sea surface temperatures, coupled with a significant eustatic sea-level fall recorded on all corresponding paleocontinents, point to a major glaciation in polar and subpolar Gondwana which is denominated here as the "Mid-Ludfordian Glaciation". The onset of rapid cooling in the Prague Basin (peri-Gondwana) is preceded by the deposition of shales enriched in redox-sensitive trace metals suggesting that anoxic/euxinic waters expanded on the deeper carbonate shelf just before the MLCIE. The coincidence of culmination of the anoxic event (named here as the Siluricus Ocean Anoxic Event) with the Lau/Kozlowskii extinction events is documented for the first time outside of the Laurussian epeiric basins. Widespread oxygen deficient conditions are interpreted to have been stressful to shelfal ecosystems and may have been a major cause of the extinctions. The mid-Ludfordian glacio-eustatic sea-level fall caused a reduction of shelf habitats culminating in a lower faunal diversity and a change in the structure of faunal communities. The observed positive delta O-18(apatite) excursion is tightly coupled to delta C-13 and delta S-34 anomalies documented from temperate (peri-Gondwana) as well as tropical (Laurussia) paleolatitudes. The delta O-18(apatite) data complete the Silurian seawater temperature curve and show evidence that one of the largest positive carbon isotope anomalies (MLCIE) of the Phanerozoic was preceded by a widespread anoxic event and tightly linked with a climate cooling event as documented as well for most other Silurian CIEs.