Urban development substantially alters the physicochemistry of streams, resulting in biodiversity and ecosystem function loss. However, interregional comparisons of physicochemical impact in urban streams suggest that geoclimatic heterogeneity may influence the extent of degradation. In the Mid-Atlantic United States, the adjacent Coastal Plain and Piedmont physiographic provinces possess distinctly different hydrogeomorphic properties that may influence how stream ecosystems respond to urbanization. Recent bioassessments have demonstrated that biotic sensitivity to urbanization is relatively acute in the Piedmont, suggesting that physicochemical change as a consequence of urbanization may be greater in that province. We compared hydrologic, chemical, and thermal characteristics of Mid-Atlantic Coastal Plain and Piedmont first- through fifth-order streams along gradients of impervious surface cover (ISC) at multiple spatial scales. Linear models were applied to test if conditions in rural streams and the degree of impact from ISC varied between provinces. Mean and maximum summer temperatures in Piedmont streams increased more per unit of ISC than in the Coastal Plain. Contrary to expectations, however, variables that quantified high-flow event frequency, magnitude and duration, exhibited significantly greater impact along the ISC gradient in the Coastal Plain. Most chemical changes associated with increasing ISC were similar in the two provinces, although the interregional chemical composition of rural streams differed substantially for most parameters. Our findings demonstrate consistent interregional heterogeneity in stream ecosystem responses to urbanization. Landscape-scale management decisions with stream ecosystem conservation, mitigation, or restoration as a goal must therefore carefully consider the geoclimatic context in order to maximize effectiveness.