Modelling the complex nature of regional knowledge creation is high on the research agenda. It deals with the identification of drivers for regional knowledge creation of different kinds, among them inter-regional networks and agglomeration factors, as well as their interplay; i.e., in which way they influence regional knowledge creation and accordingly, innovation capabilities—in the short- and long-term. Complementing a long line of tradition—establishing a link between regional knowledge input indicators and knowledge output in a regression framework—we propose an empirically founded agent-based simulation model that intends to approximate the complex nature of the multi-regional knowledge creation process for European regions. Specifically, we account for region-internal characteristics, and a specific embedding in the system of region-internal and region-external R&D collaboration linkages. With first exemplary applications, we demonstrate the potential of the model in terms of its robustness and empirical closeness. The model enables the replication of phenomena and current scientific issues of interest in the field of geography of innovation and hence, shows its potential to advance the scientific debate in this field in the future.