Abstract: As an important region underpinning ecological security and water-resource balance in northern China, the Loess Plateau’s ecohydrological regulation plays a pivotal and strategic role in ensuring water security across the Yellow River Basin. However, in the wake of large-scale ecological restoration, the region has been confronted with a complex combination of both emerging and historical challenges, such as vegetation degradation, progressive soil desiccation, and abrupt declines in runoff and sediment yield. The conventional single-objective regulation model centered on “soil conservation and greening” is now inadequate for the realities of multi-objective and coordinated management. This study demonstrated the necessity of a paradigm shift from a “soil conservation and greening” focus toward a system-equilibrium framework that integrates water, ecological, economic, and social dimensions. The core content of this paradigm innovation was proposed across five dimensions (objectives, concepts, scales, assessment, and governance), and an enabling pathway was established based on an intelligent, closed-loop technological system encompassing “sensing—cognition—prediction—regulation.” Building on this framework, five priority frontiers in fundamental science requiring breakthrough advances were identified: deep vadose-zone water cycling, vegetation water-use adaptability, rebalancing of water–sediment regimes, coupled water–carbon–nitrogen processes, and socio-ecological system modeling. This study provides a scientific foundation and decision-making reference for integrating ecological conservation and water security on the Loess Plateau. Future progress will depend on the coordinated advancement of science and technology, policy instruments, and engineering interventions to support high-quality regional development and the long-term goal of harmonious human—water relations.