Extreme hydroclimatic variability in a changing climate and the possible causes of extreme hydrological variability are essential for effectively mitigating floods. The study aims to investigate the variability of extreme hydroclimatic conditions and the relationship between anomalies in extreme local precipitation, ENSO indicators (Southern Oscillation index (SOI), Niño 3.4, and multivariate ENSO index (MEI)), and extreme flow indices in the Upper Awash River basin, Ethiopia. The analysis used standardized anomaly index and coefficient of variation statistics to examine variability, the modified Mann-Kendall and Pettitt tests for trend and change point analysis, and Spearman’s correlation test to explore relationships. The study revealed that the basin-wise extreme precipitation indices had less variability but higher variability spatially, while the extreme flow indices showed high variability. Furthermore, the basin experienced extreme wet to normal wet conditions in the 1990s compared to the 2000s. The maximum temperature increased significantly, while the minimum temperature decreased significantly (except at a few northwest stations), with a considerable shift in the 1990s and 2000s. Anomalies, extreme to normal wet conditions, and a decrease in extreme precipitation were consistent with the extreme flow at the basin outlet, Hombole station. However, the extreme flow indices at Melka Kunture increased significantly and shifted upward (2003/2005), and the anomalies in extremely wet and very wet precipitation in the northwest were possibly responsible for this change. The study also revealed that the annual wet and very wet days of precipitation strongly affected the extreme flow in the basin. The effect of annual wet day precipitation, annual maximum precipitation, and ENSO anomalies on extreme flow at the Hombole was significant. These findings enhance the understanding of extreme hydroclimatic variability and prospective flood predictability and aid flood risk management.