The integration of stratigraphic, geochemical, and biostratigraphic data from Middle Ordovician carbonates and shales indicates that the North American epeiric sea was partitioned into shelf areas with distinct characteristics. The Upper Mississippi Valley part of the epeiric sea was appraised by using regionally traceable and geochemically “fingerprinted” K-bentonites, as well as detailed lithologic correlation. In the Midcontinent, the Decorah Formation records a time of high clastic sediment influx and abundant freshwater runoff from the Transcontinental Arch that created a salinity-stratified water column and led to episodic dysoxia. Later, relative flooding of the clastic source areas greatly reduced both the clastic sediment and freshwater runoff. As a result, the salinity stratification broke down, oxygenating the seafloor and permitting carbonates to form. Associated with this change, clarity of the water improved and the photic zone expanded, allowing seasonal blooms of Gloeocapsomorpha prisca to occur, resulting in increased burial of organic matter. The increase in G. prisca and total organic carbon coincided with, but lagged behind, a regional δ13C excursion. In addition, the timing of the initiation of the isotopic anomaly is different across the studied area, suggesting that local environmental conditions influenced the isotopic record. Data presented in this study support the partitioning of distinct areas within epeiric seas and the importance of this setting in storing inorganic and organic carbon and recording environmental and biological changes.