To evaluate recent Ordovician paleogeographic reconstructions, ε_Nd values were determined in conodonts as a proxy for the isotopic variations in ancient seawater using samples from the major cratons and microplates. Isotopic variations reveal the existence of distinct oceanic masses and epeiric seas that constrain the position of plates and terranes relative to these water masses and hence constrain models of regional and global paleogeography. The isotopic patterns show a consistent picture of the changes in the Ordovician oceans. The ε_Nd values for water masses associated with Laurentia are strongly negative (−28 to −18) in the Early Ordovician, evolving over time to higher values in the range −13 to −5. The Early Ordovician signature of Laurentia is in marked contrast to other cratons and microplates, which have a range of values from −10 to −5. Samples from South China show interesting signals that reflect a greater similarity to Laurentia than other peri-Gondwana terranes. The isotopic variations are a function of both regional geology and global tectonic processes, the most obvious being the Taconic Orogeny and onset of the closure of the Iapetus Ocean. Regional and global models of paleogeography are considered in light of these proxy signals. This study also reveals that conodonts are powerful geochemical tools for obtaining information on ancient water masses. The use of the Nd isotopic signatures from conodonts provides a method independent of paleomagnetism and biogeography to test paleogeographic models. By integrating such information, a more multidisciplinary approach is possible.