We report a large, positive, carbon isotope excursion in the Kinderhookian Stage of the Lower Mississippian in North America and propose that the excursion is linked to the Antler orogeny. The δ13C excursion reaches +7.1‰ in the upper part of the Joana Limestone in southeast Nevada and correlates with peaks recognized in Europe and elsewhere in North America. This isotopic shift, one of the largest known Phanerozoic δ13C events, is found within the upper part of the Siphonodella isosticha–Upper crenulata conodont Zone; its formation coincided with a time of rapid subsidence of the Joana platform within the Antler foreland basin. We interpret the large changes in δ13C values to reflect enhanced organic carbon burial rates in response to tectonic deepening followed by creation of a restricted water mass at depth in the Antler foredeep and other foredeeps of similar age. The presence of a large δ13C excursion in the upper part of the S. isosticha Zone is consistent with a late Kinderhookian (Tournaisian) glacial episode.