Higher education institutions (HEIs) could act as pivotal change agents for sustainable development (SD) in times of global climate action. However, HEIs have to respond to increasingly complex demands simultaneously, such as massification, globalization, marketization, and digitalization. Based on Graves’ model of systemic development, this paper discusses two main strategies to deal with increased complexity in order to meet the challenge of SD: (a) Promoting general systemic development of a given HEI, progressively opening up to various stakeholders and focusing on co-creative collaboration, and (b) participating in inter-organizational networks to find inspiration for dealing with challenging trends. Four distinct phases of higher education development are presented. It is argued that transdisciplinary research and research-based learning will increasingly be needed for tackling societal issues and that HEIs should address different organizational subsystems individually. Furthermore, four types of inter-organizational networks are proposed and implications for network management are discussed. A case study of the HOCH-N network illustrates the practical application of the presented ideas. Finally, adopting a multi-dimensional and networked organizational model as an integrative University 4.0 is argued to be suitable for increasing the capacity to deal with complexity, thus meeting the challenge of sustainable development.