Abstract: The water–energy–food (WEF) nexus can be closely interconnected with the production, allocation, and consumption of water, energy, and food in sustainable agriculture. One subsystem also strongly affects the others. Accordingly, the WEF nexus can improve the resource use efficiency under increasing resource scarcity and environmental pressure. A typical region, the middle and lower reaches of the Yellow River Basin (MLYR), is characterized by water scarcity, energy consumption, food production, and environmental constraints. From the WEF nexus perspective, total factor productivity (TFP) is expected to promote high-quality regional development and integrated resource governance under the dual pressures of rigid water constraints and limited environmental carrying capacity. This study aims to investigate the spatiotemporal evolution and driving mechanism of total factor productivity in the Middle and Lower reaches of the Yellow River using the water-energy-food nexus. Two scenarios were constructed, one considering undesirable outputs and another excluding them, to identify the effects of environmental constraints on TFP measurement. The slack-based measure directional distance function combined with the global Malmquist–Luenberger (SBM-DDF-GML) index was employed to evaluate the spatiotemporal evolution of urban TFP in the MLYR from 2010 to 2021. Dynamic productivity was captured to incorporate undesirable outputs, such as pollution emissions. Thereby, the efficiency evaluation framework was provided under environmental constraints. In addition, partial least squares regression (PLSR) was applied to identify the key factors driving TFP dynamics for the mechanism of efficiency evolution. The results show that urban TFP exhibited an overall upward trend during 2010–2021, indicating gradual advancement in resource allocation, production conditions, and technology. There were outstanding differences in magnitude and spatial pattern under the two scenarios. TFP with undesirable outputs (TFP_u) ranged from 0.701 to 1.000, whereas conventional TFP without undesirable outputs (TFP_c) ranged from 0.823 to 1.000. Furthermore, TFP_u was consistently lower than TFP_c among cities in the study period, and the average TFPu value (0.941) was also lower than the average TFPc value (0.957). Actual productivity was then overestimated without considering environmental costs, whereas the undesirable outputs provided a more reliable assessment of development quality. Spatially, TFP_u generally shared a decreasing pattern from west to east, indicating stronger environmental constraints and lower resource use efficiency in the eastern region, when considering pollution. By contrast, TFP_c displayed the higher-level pattern in the peripheral areas, whereas the lower levels were in the central region. Environmental constraints significantly reshaped the spatial pattern of productivity. The driving mechanism analysis further showed that the growth in desirable outputs and improvements in resource utilization efficiency were the main contributors to TFP enhancement, whereas undesirable outputs exerted a persistent inhibitory effect. Overall, the environmental constraints can redefine the assessment and evolution of resource use efficiency. The findings can also provide quantitative evidence to coordinate the water saving, pollution reduction, and resource optimization in the Yellow River Basin.