Sedimentary basins throughout the North American Western Interior contain a record of Late Cretaceous through Eocene deposition related to the Laramide orogeny. The typical stratigraphic progression includes an uppermost Cretaceous fluvio-deltaic geologic formation that is unconformably overlain by an alluvial or paludal Paleocene geologic formation. The Paleocene unit is usually characterized by drab overbank facies, and overlain by an interval of amalgamated fluvial sand bodies. The overlying Eocene geologic units are characterized by red bed overbank facies. These major stratigraphic changes have been variably linked to long-wavelength dynamic subsidence, local uplift, and climatic shifts. Herein, we evaluate the depositional history of the Huerfano Basin of south-central Colorado in this overarching context. Our study presents a detailed lithofacies analysis of the Poison Canyon, Cuchara, and Huerfano Formations integrated with a new bulk (1) organic carbon isotope record, n = 299 measurements (Data Supplement 1A); and (2) magnetic record, n = 247 measurements (Data Supplement 1B). We interpret that the Paleocene Poison Canyon Formation was deposited by a braided or coarse-grained meandering river system with relatively poorly drained floodplains. The Eocene Huerfano Formation was likely deposited by a coarse-grained meandering river system with a comparatively well-drained floodplain. This pattern mirrors other Laramide basins, and is likely related to a regional drying pattern linked to long-term warming during the early Paleogene. Age of the intervening Cuchara Formation is poorly resolved, but is an anomalously thick and coarse-grained fluvial unit, with evidence for extensive reworking of floodplain deposits and a moderate coarsening-upward pattern. The Cuchara Formation is associated with magnetic trends that suggest greater oxidation and weathering, and greater variability in rainfall patterns, as well as a subtle negative shift in carbon isotope values. This pattern indicates a period of widespread progradation within the basin, potentially related to a major Laramide uplift event that affected Colorado’s Wet Mountains, Front Range, and Sangre de Cristo Mountains.