The aim of this paper is to propose a research framework, based on the joint use of three widely used methods: EMergy Evaluation (EME), Ecological Footprint Analysis (EFA) and Greenhouse Gas Inventory (GHGI), that are applied to assess the environmental sustainability of a region. The results of application of these methods to several Italian Provinces enabled us to compare their sustainability, and to test the methods with respect to sustainability requirements at local and global level. The outcomes suggest that the proposed framework provides an organic evaluation of regional systems based on key aspects, such as resources depletion, consumption patterns, waste production and absorption.