Silurian strata of eastern North America have been thoroughly studied for nearly two centuries. Through these investigations a general understanding of unit distribution and correlative relationships were established throughout the region. Many of these interpretations remain valid still to this day, however, with advancements in stratigraphic methodologies in the last few decades (e.g., sequence-, chemo-, and biostratigraphy), numerous discrepancies have come to light with regards to the chronostratigraphic correlation of several stratigraphic intervals throughout the region. A number of these discrepancies within the lower Silurian (Llandovery—lower Wenlock) have been resolved in the last two decades permitting the establishment of refined depositional models and sequence stratigraphic hierarchies for strata deposited during this interval of time for the Appalachian, Illinois, and Michigan basins. Though these studies provided significant improvement to the chronostratigraphy of eastern North America, there remained a large under-evaluated stratigraphic interval spanning the remainder of the Silurian (Wenlock—Pridoli), which is host to expansive evaporite reserves and hydrocarbon resources throughout eastern North America. As such, it is critical that these strata are accurately and precisely correlated throughout the region and that temporal constraint be applied to these resources in order to evaluate their potential and develop predictive models for their future utilization. The investigation herein provides high-resolution chronostratigraphic analyses of several core and outcrop from the eastern, southwestern, and western margins of the Appalachian Basin. These analyses included the integration of δ13Ccarb chemostratigraphy, conodont biostratigraphy, sequence stratigraphy, and subsurface geophysical data. The work herein now permits the establishment of global series and stage boundaries for the upper Silurian throughout the Appalachian and Michigan basins and also addresses regional miscorrelations within strata on both the eastern and western margins of the Appalachian Basin to provide a united sequence stratigraphic hierarchy between the Appalachian, Illinois, and Michigan basins.