In the interior western United States, increased demand for water coupled with the uncertain nature of anthropogenic and natural hydroclimatic variations add challenges to the task of assessing the adequacy of the existing regional water resources systems. Current availability of relatively short instrumental streamflow records further limits the diagnosis of multidecadal and longer time variations. Here we develop a long-term perspective of streamflow variations using a 285-year long tree-ring reconstruction at Middle Boulder Creek, Colorado. Analysis of the reconstructed streamflow provides useful insights for assessing vulnerability: (a) a wider range of hydrologic variations on multidecadal time scales, not seen in the instrumental record, (b) wet/dry regimes show disparate fluctuations across various flow thresholds, and (c) temporal changes in the flow probabilities have varied flavors corresponding to wet and dry regimes and their spatial extent. Based on these results, we discuss implications for the climate-related vulnerability of regional water resources.