Salinity variation in ancient epicontinental seas has long been challenging to reconstruct. We determined salinity variation in the Late Pennsylvanian North American Midcontinent Sea based on normalized boron concentrations (B/Ga) and isotopic compositions (δ11B) of bulk shale. We analyzed the Stark Shale Member of the Missourian Stage Dennis Limestone cyclothem in the Charleston core (CC) from the Illinois Basin (eastward, more proximal) and the Iowa Riverton core (IRC) from the Midcontinent Shelf (westward, more distal). Both cores exhibited the same pattern of secular variation, with lower B/Ga and δ11B values at their base and top, recording less saline conditions during lower sea-level stands, and higher values in their middle part, recording more saline conditions at highstands—a pattern that conforms to conventional sequence stratigraphic and glacio-eustatic interpretations of Midcontinent cyclothems. At equivalent stratigraphic levels, B/Ga and δ11B values are systematically lower at CC relative to IRC, reflecting the generally lower salinity conditions of the Illinois Basin relative to the Midcontinent shelf, which is consistent with greater freshwater influence from the east due to heavy river runoff into the Appalachian foreland basin. Our findings serve to demonstrate the utility of paired B concentration and isotope data for paleosalinity analysis of deep-time shale formations.