Collaborative networks and open innovation have high potential as co-drivers of value creation for many production and service sectors such as education. In higher education, it is increasingly frequent to observe universities implementing teaching-learning systems with collaborative processes supported by 4.0 technologies. Moreover, various pedagogical procedures, research activities, and co-development projects have complemented these types of collaborative processes, which today are considered desirable to be carried out within Education 4.0.In this paper, the authors propose a reference framework for designing new teaching-learning systems using the concept and vision of Education 4.0. The proposed reference framework considers key enablers of Education 4.0 and three dimensions to analyse and evaluate decisions made: (i) Technological, (ii) Pedagogical, and (iii) Organisational. Finally, two case studies involving collaborative networks and open innovation illustrate how the proposed reference framework is used.