The impacts of extreme weather events on water–carbon (C) coupling and ecosystem-scale water use efficiency (WUE) over a long term are poorly understood. We analyzed the changes in ecosystem water use efficiency (WUE) from 10 years of eddy-covariance measurements (2004–2013) over an oak-dominated temperate forest in Ohio, USA. The aim was to investigate the long-term response of ecosystem WUE to measured changes in site-biophysical conditions and ecosystem attributes. The oak forest produced new plant biomass of 2.5 ± 0.2 g C kg−1 of water loss annually. Monthly evapotranspiration (ET) and gross ecosystem production (GEP) were tightly coupled over the 10-year study period (R2 = 0.94). Daily WUE had a linear relationship with air temperature (Ta) in low-temperature months and a unimodal relationship with Ta in high-temperature months during the growing season. On average, daily WUE ceased to increase when Ta exceeded 22 °C in warm months for both wet and dry years. Monthly WUE had a strong positive linear relationship with leaf area index (LAI), net radiation (Rn), and Ta and weak logarithmic relationship with water vapor pressure deficit (VPD) and precipitation (P) on a growing-season basis. When exploring the regulatory mechanisms on WUE within each season, spring LAI and P, summer Rn and Ta, and autumnal VPD and Rn were found to be the main explanatory variables for seasonal variation in WUE. The model developed in this study was able to capture 78% of growing-season variation in WUE on a monthly basis. The negative correlation between WUE and P in spring was mainly due to the high precipitation amounts in spring, decreasing GEP and WUE when LAI was still small, adding ET being observed to increase with high levels of evaporation as a result of high SWC in spring. Summer WUE had a significant decreasing trend across the 10 years mainly due to the combined effect of seasonal drought and increasing potential and available energy increasing ET, but decreasing GEP in summer. We concluded that seasonal dynamics of the interchange between precipitation and drought status of the system was an important variable in controlling seasonal WUE in wet years. In contrast, despite the negative impacts of unfavorable warming, available groundwater and an early start of the growing season were important contributing variables in high seasonal GEP, and thus, high seasonal WUE in dry years.