Abstract: Attract: Water, energy, and food are fundamental pillars of human survival, economic growth, and long-term social stability. Their production, allocation, and consumption are closely interconnected, forming the water–energy–food (WEF) nexus, in which changes in one subsystem can strongly affect the others. Accordingly, in regions facing increasing resource scarcity and environmental pressure, understanding the WEF nexus is essential for improving resource use efficiency and promoting sustainable development. The middle and lower reaches of the Yellow River Basin (MLYR) are a typical region where water scarcity, energy consumption, food production, and environmental constraints coexist. Under the dual pressures of rigid water constraints and limited environmental carrying capacity, investigating total factor productivity (TFP) from the WEF nexus perspective is of great significance for promoting high-quality regional development and improving integrated resource governance. To address this issue, this study constructed two comparative scenarios, one considering undesirable outputs and the other 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. This method captures dynamic productivity changes while incorporating undesirable outputs such as pollution emissions into the efficiency evaluation framework, thereby providing a more realistic assessment under environmental constraints. In addition, partial least squares regression (PLSR) was applied to identify the key factors driving TFP dynamics and to reveal the underlying mechanism of efficiency evolution. The results show that urban TFP in the MLYR exhibited an overall upward trend during 2010–2021, indicating gradual improvement in resource allocation, production conditions, and technological progress. However, clear differences in magnitude and spatial pattern emerged under the two scenarios. TFP considering 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. Across the study period and among cities, TFP_u was consistently lower than TFP_c, and the average TFP_u value (0.941) was also lower than the average TFP_c value (0.957). This indicates that ignoring environmental costs may overestimate actual productivity, whereas incorporating undesirable outputs provides a more realistic and prudent assessment of development quality. Spatially, TFP_u generally showed a decreasing pattern from west to east, suggesting stronger environmental constraints and lower resource use efficiency in the eastern part of the study area under pollution-inclusive conditions. By contrast, TFP_c displayed a pattern of relatively higher levels in peripheral areas and lower levels in the central region. This difference indicates that environmental constraints significantly reshape the spatial pattern of productivity evaluation. The driving mechanism analysis further showed that 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, this study clearly demonstrates that environmental constraints play a critical role in reshaping both the assessment and evolution of resource use efficiency, and it provides quantitative evidence for promoting coordinated strategies of water saving, pollution reduction, and resource optimization in the Yellow River Basin.