Groundwater is a critical resource in the Grand Canyon region, supplying nearly all water needs for residents and millions of visitors. Additionally, groundwater discharging at hundreds of spring locations in and near Grand Canyon supports important ecosystems in this mostly arid environment. The security of groundwater supplies is of critical importance for both people and ecosystems in the region and the potential for changes to groundwater systems from projected climate change is a cause for concern. In this study, we analyze recent historical and projected precipitation and temperature data for the Grand Canyon region. Projected climate scenarios are then used in Soil Water Balance groundwater infiltration simulations to understand the state-of-the-science on projected changes to groundwater resources in the area. Historical climate data from 1896 through 2019 indicate multi-decadal cyclical patterns in both precipitation and temperature for most of the time period. Since the 1970s, however, a significant rising trend in temperature is observed in the area. All 10-year periods since 1993 are characterized by both below average precipitation and above average temperature. Downscaled and bias-corrected precipitation and temperature output from 97 CMIP5 global climate models for the water-year 2020–2099 time period indicate projected precipitation patterns similar to recent historical (water-year 1951–2015) data. Projected temperature for the Grand Canyon area, however, is expected to rise by as much as 3.4 °C by the end of the century, relative to the recent historical average. Integrating the effects of projected precipitation and temperature changes on groundwater infiltration, simulation results indicate that > 76% of future decades will experience average potential groundwater infiltration less than that of the recent historical period.