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The development of a comprehensive sustainability analysis tool for evaluating regional urban systems would present researchers, planners, and policy makers with a powerful tool to study and manage systems, with the goal of encouraging optimum social and economic trends, while maintaining long-term environmental protection that leads to sustainability. This article intends to aid in this effort by presenting a versatile methodology for assessing sustainability as a function of dynamic changes in significant characteristics of urban systems. Using statistical methods, this work presents a strategy for comparatively assessing the impact of social and economic characteristics on system stability at geographic scales which are critical to policy and management. Specifically, it employs the Fisher Information index as a measure of sustainability, in order to distinguish periods of stability. As an application of the approach, six Metropolitan Statistical Areas (MSAs) in Ohio (Cincinnati, Dayton, Cleveland, Akron, Columbus, and Toledo) were evaluated for a regional sustainability assessment. Results from the multiyear analysis suggest two distinct periods in these MSAs: one characterized by 30 years of socio-economic growth (1970-1999) and another (2000-2009) denoting a change in the trajectory of each system found to be related to economic recession. Columbus was identified as the most stable and sustainable of the MSAs during the study period. In contrast, Toledo exhibited the largest changes in economic trends, as distinguished by excessive increases in the growth rate of vacant housing units, unemployed civilian labor force, and inhabitants below the poverty level (2000-2009). Since such conditions are not desirable for urban systems, they are indicative of movement towards an unsustainable future.