A fundamental goal of intraplate tectonics research is to understand the role of crustal discontinuities in the distribution of Quaternary surface ruptures. Geophysical studies of southern North America on the Gulf of Mexico Coastal Plain reveal a buried Cambrian craton margin (Alabama-Oklahoma transform) that strikes southeast beneath Mesozoic and Cenozoic passive-margin sediments and Paleozoic thrust sheets. Seismic-reflection profiles show a graben system (Saline River fault zone) related to an episode of Triassic rifting above this transform margin during initial opening of the Gulf of Mexico. Post-Triassic reactivation of the Saline River fault zone produced normal and reverse faulting and strike-slip flower structures that can be linked to Quaternary surface deformation. We investigated surface and shallow Quaternary faulting along the Saline River fault system in south-central North America. Our field sites show late Pleistocene to late Holocene surface and near-surface deformation along lineaments and scarps of the Saline River fault zone. Age constraints from three sites are consistent with a surface rupture as long as 70 km ca. 6–5 ka. Mid-Holocene sand blows in the region may record strong shaking from such a large earthquake about the same time, but available ages provide only broad constraints on the timing of large earthquakes in the Saline River fault zone. The Saline River fault zone significantly expands the known area of paleoseismicity in midcontinent North America. This study builds upon our understanding of the Saline River fault zone's relationship to a transform craton margin and thus advances our understanding of active intraplate deformation.