Understanding the impact of climate change on water resources is important for developing regional adaptive water management strategies. This study investigated the impact of climate change on water resources in the Yarmouk River Basin (YRB) of Jordan by analyzing the historical trends and future projections of temperature, precipitation, and streamflow. Simple linear regression was used to analyze temperature and precipitation trends from 1989 to 2017 at Irbid, Mafraq, and Samar stations. The Statistical Downscaling Model (SDSM) was applied to predict changes in temperature and precipitation from 2018 to 2100 under three Representative Concentration Pathway (RCP) scenarios (i.e., RCP2.6, RCP4.5, and RCP8.5), and the Soil and Water Assessment Tool (SWAT) was utilized to estimate their potential impact on streamflow at Addasiyia station. Analysis of data from 1989 to 2017 revealed that mean maximum and minimum temperatures increased at all stations, with average rises of 1.62°C and 1.39°C, respectively. The precipitation trends varied across all stations, showing a significant increase at Mafraq station, an insignificant increase at Irbid station, and an insignificant decrease at Samar station. Historical analysis of streamflow data revealed a decreasing trend with a slope of −0.168. Significant increases in both mean minimum and mean maximum temperatures across all stations suggested that evaporation is the dominant process within the basin, leading to reduced streamflow. Under the RCP scenarios, projections indicated that mean maximum temperatures will increase by 0.32°C to 1.52°C, while precipitation will decrease by 8.5% to 43.0% throughout the 21st century. Future streamflow projections indicated reductions in streamflow ranging from 8.7% to 84.8% over the same period. The mathematical model results showed a 39.4% reduction in streamflow by 2050, nearly double the SWAT model’s estimate under RCP8.5 scenario. This research provides novel insights into the regional impact of climate change on water resources, emphasizing the urgent need to address these environmental challenges to ensure a sustainable water supply in Jordan.