The Yellow River Basin (YRB) is an important grain and energy production base in China. However, the sustainable development of the YRB is constrained by water scarcity. Identifying the key factors influencing water use changes through the lens of the Water-Energy-Food Nexus (WEF-Nexus) is essential for sustainable resource use in the YRB. This study analyzed the spatial and temporal changes in water use in the energy and food sectors from 2000 to 2020 and identified the key factors influencing water use changes based on the generalized Divisia index method. Then, the water use change induced by the WEF-Nexus was evaluated. The results indicated that (1) the scale of energy production is the key factor leading to increased water use, with a total contribution of 21.345 billion m3 from 2000 to 2020. The intensity of energy water use is the key factor in inhibiting increased water use, reducing regional water use by 18.853 billion m3. (2) In the past 20 years, the changes in water use by energy and food production in the midstream and downstream regions showed nonsignificant downward trends and upward trends in the upstream region. Thus, the stability and sustainability of water use downstream have strengthened, while the water use sustainability upstream and the stability of water use midstream should further increase. This paper will support sustainable water use in the YRB.