University spin-offs (USOs) are companies created to commercialize knowledge or technology developed in academia; thus, their major contribution to the knowledge economy is their ability to generate innovation. Following the Resource-Based View of the Firm and the Knowledge Spillover Theory of Entrepreneurship, it was stated that fostering mechanisms at university level and at regional level may positively influence the USOs innovation. Based on a sample of 621 Italian USOs, we show that the positive impact of the university context is more crucial compared with those of the regional context. In particular, the university affiliated business incubators and Science Parks, jointly with the university financial resources, seem to promote the innovation efforts of USOs. These evidences rise the need of a resilient partnership among all the contextual players involved in the spillover processes, mainly at regional level, in order to effectively exploit the potential innovative efforts of the university start-ups.