Higher education institutions (HEIs) contribute substantially to the quality of life (QoL) of the regions where they operate and to the progress and sustainable development of a country. This research intends to have an innovative approach in the study of the HEIs' impact on the QoL of regions by taking into consideration both qualitative and quantitative indicators. This study aims to identify, collect and systematize indicators that can be used to measure the impact of HEIs on QoL: on the demand-side based on expenditure (inputs) and the knowledge-based supply side (outputs). For accomplishing this, the authors carried out a literature review, an analysis of available statistical data in Portugal and interviews for the analysis and consolidation of indicators. The results will facilitate the measurement of the HEIs' impact on QoL and regions and allow the elaboration of a matrix of reliable indicators, which will hopefully assist in the definition of new higher education policies.