Alterations to flow regimes from regulation and climatic change both affect the biophysical functioning of rivers over long time periods and large spatial areas. Historically, however, the effects of these flow alteration drivers have been studied separately. In this study, results from unregulated and regulated river management models were assessed to understand how flow regime alterations from river regulation differ under future climate conditions in the Sierra Nevada of California, USA. Four representative flow alteration metrics—mean annual flow, low flow duration, centroid timing and mean weekly rate of decrease—were calculated and statistically characterized under historical and future unregulated and regulated conditions over a 20-year period at each of the eight regulated river locations below dams across the Sierra Nevada. Future climatic conditions were represented by assuming an increase in air temperature of 6 °C above historical (1981–2000) air temperatures, with no change in other meteorological conditions. Results indicate that climate warming will measurably alter some aspects of the flow regime. By comparison, however, river regulation with business-as-usual operations will alter flow regimes much more than climate warming. Existing reservoirs can possibly be used to dampen the anticipated effects of climate warming through improved operations, though additional research is needed to identify the full suite of such possibilities.