The frequency and character of Southern California’s Santa Ana wind events are investigated within a 12-km-resolution downscaling of late-20th and mid-21st century time periods of the National Center for Atmospheric Research Community Climate System Model global climate change scenario run. The number of Santa Ana days per winter season is approximately 20% fewer in the mid 21st century compared to the late 20th century. Since the only systematic and sustained difference between these two periods is the level of anthropogenic forcing, this effect is anthropogenic in origin. In both time periods, Santa Ana winds are partly katabatically-driven by a temperature difference between the cold wintertime air pooling in the desert against coastal mountains and the adjacent warm air over the ocean. However, this katabatic mechanism is significantly weaker during the mid 21st century time period. This occurs because of the well-documented differential warming associated with transient climate change, with more warming in the desert interior than over the ocean. Thus the mechanism responsible for the decrease in Santa Ana frequency originates from a well-known aspect of the climate response to increasing greenhouse gases, but cannot be understood or simulated without mesoscale atmospheric dynamics. In addition to the change in Santa Ana frequency, we investigate changes during Santa Anas in two other meteorological variables known to be relevant to fire weather conditions—relative humidity and temperature. We find a decrease in the relative humidity and an increase in temperature. Both these changes would favor fire. A fire behavior model accounting for changes in wind, temperature, and relative humidity simultaneously is necessary to draw firm conclusions about future fire risk and growth associated with Santa Ana events. While our results are somewhat limited by a relatively small sample size, they illustrate an observed and explainable regional change in climate due to plausible mesoscale processes.