The 21st century is marked by increasing systemic entropy, characterized by rapid technological shifts, environmental crises, and geopolitical instability. Regional science, originally born as an interdisciplinary field capable of addressing complex, abstract socio-spatial phenomena, has drifted toward applied, hyper-specific methods, leaving its theoretical core underdeveloped and the concept of the region poorly defined. This paper argues for a revitalization of regional science through a return to its general systems roots. By re-engaging with early theoretical frameworks, regional science can better analyze contemporary challenges, particularly hybrid warfare dynamics. Hybrid warfare’s reliance on disinformation, economic coercion, attacks on critical infrastructure, and weaponization of migration presents uniquely socio-spatial and systems-oriented problems. This paper proposes a dual approach: strengthening the theoretical branch of regional science to delineate warfare dynamics conceptually, while supporting applied scholars in operationalizing these insights. Rebuilding the theoretical foundation could reposition regional science as a distinct and essential discipline in the entropic age.