This paper study the role of higher education and universities in building regional competitiveness through innovation. The research focuses specifically on the role of innovation centers design and operation considering sustainable development to provide a sustainable operative innovation and entrepreneurship activities. The research shows innovation and knowledge creation as drivers for regional competitiveness; it shows the role universities and its mission as a fourth-generation universities fostering that. The research moves forward to provide some examples and models for international innovation centers at different universities. The research focus on innovation and entrepreneurship pillar in Egyptian higher education strategy and its corelation with sustainability pillar. The research show Ain shams university innovation center as a case study and briefly shows the building design as an EDGE advanced certified sustainable building offering various services for innovation and entrepreneurial activities and fostering innovation ecosystem within the university.