One of the enduring questions in the field of paleohydrology is how quickly desert wetland ecosystems responded to past episodes of abrupt climate change. Recent investigations in the Las Vegas Valley of southern Nevada have revealed that wetlands expanded and contracted on millennial and sub-millennial timescales in response to changes in climate during the late Quaternary. Here, we evaluate geologic evidence from multiple localities in the Mojave Desert and southern Great Basin that suggests the response of wetland systems to climate change is even faster, occurring at centennial, and possibly decadal, timescales. Paleowetland deposits at Dove Springs Wash, Mesquite Springs, and Little Dixie Wash, California, contain evidence of multiple wet and dry cycles in the form of organic-rich black mats, representing periods of past groundwater discharge and wet conditions, interbedded with colluvial, alluvial, and aeolian sediments, each representing dry conditions. Many of these wet-dry cycles date to within the Younger Dryas (YD) chronozone (12.9–11.7 ka), marking the first time intra-YD hydrologic variability has been documented in paleowetland deposits. Our results illustrate that desert wetland ecosystems are exceptionally sensitive to climate change and respond to climatic perturbations on timescales that are relevant to human society.