Academic entrepreneurship by means of university spin-offs commercializes technological breakthroughs, which may otherwise remain unexploited. However, many universities face difficulties in creating spin-offs. This article adopts a science-based design approach to connect scholarly research with the pragmatics of effectively creating university spin-offs. This approach serves to link the practice of university spin-off creation, via design principles, to the scholarly knowledge in this area. As such, science-based design promotes the interplay between emergent and deliberate design processes. This framework is used to develop a set of design principles that are practice based as well as grounded in the existing body of research on university spin-offs. A case-study of spin-off creation at a Dutch university illustrates the interplay between initial processes characterized by emergent design and the subsequent process that was more deliberate in nature. This case study also suggests there are two fundamentally different phases in building capacity for university spin-off creation. First, an infrastructure for spin-off creation (including a collaborative network of investors, managers and advisors) is developed that then enables support activities to individual spin-off ventures. This study concludes that to build and increase capacity for creating spin-offs, universities should do the following: (1) create university-wide awareness of entrepreneurship opportunities, stimulate the development of entrepreneurial ideas, and subsequently screen entrepreneurs and ideas by programs targeted at students and academic staff; (2) support start-up teams in composing and learning the right mix of venturing skills and knowledge by providing access to advice, coaching, and training; (3) help starters in obtaining access to resources and developing their social capital by creating a collaborative network organization of investors, managers, and advisors; (4) set clear and supportive rules and procedures that regulate the university spin-off process, enhance fair treatment of involved parties, and separate spin-off processes from academic research and teaching; and (5) shape a university culture that reinforces academic entrepreneurship by creating norms and exemplars that motivate entrepreneurial behavior. These and other results of this study illustrate how science-based design can connect scholarly research to the pragmatics of actually creating spin-offs in academic institutions.