Lake-level changes since ca. 3.6 kilo-annum (ka) at Emerald Lake in the Upper Arkansas River Basin of west-central Colorado coincide in time with changes of the opposite direction at Lake of the Woods in northwestern Wyoming. The contrast provides evidence of a multi-centennial moisture dipole across the Southern and Central Rocky Mountains' region similar to one associated with the effects of the El Niño Southern Oscillation (ENSO) on annual to decadal time scales today. Cores and ground penetrating radar (GPR) profiles from Emerald Lake show that deep-water muds accumulated as extensively across the lake basin as today at ca. 3.6–3.0 and 1.4–0.8 ka, and nearly as extensively at 2.5–1.9 ka. The extensive muds indicate episodes of high water at Emerald Lake and date to times when Lake of the Woods was low. Nearshore sand layers at Emerald Lake indicate that water levels fell during the intervening centuries, including when bristlecone pine chronologies have documented repeated multi-decadal droughts in the Upper Arkansas River Basin. Water levels were also low, based on the absence of nearshore mud accumulation, before ca. 3.6 ka, and dramatically lower (>2 m in the currently 4.5-m deep lake) before a sharp rise in water levels by ca. 5.7 ka. A basin-wide change in sediment accumulation patterns, consistent with an expansion and deepening of the lake at ca. 5.7 ka, correlates with regional cooling and similar evidence of increased effective moisture at Lake of the Woods and other sites throughout central North America. The step increase in moisture availability may relate to a global-scale reorganization of climatic patterns, which developed as the mid- and high-latitudes cooled in response to a decline in summer insolation.