Megaproject construction endeavors and technological innovation activities, led by industry–university–research (IUR) collaboration, demonstrate marked disparities in value orientations, implementing entities, and constituent components. These discrepancies lead to a mismatch between innovation demands and actual activities, as well as insufficient innovation motivation among construction entities, subsequently impacting innovation effectiveness and the commercialization of outcomes and failing to adequately support engineering construction needs. In response to this predicament, the academic community widely acknowledges IUR collaborative innovation as a solution. This research integrates fundamental theoretical analysis with a multi-case study approach and systematically dissects the distinctive features at the micro, meso, and macro levels, grounded in the collaborative innovation practices of IUR in three iconic railway engineering projects in China. Subsequently, it unravels the inherent operational mechanics of the IUR collaborative innovation system within large-scale projects. Specifically, at the micro level, the profound engagement of governments and project owners fosters a solid supportive environment and collaborative platform for IUR collaboration, while past successful cooperation experiences among key innovation entities enhance their technological and knowledge interactions. At the meso level, shared industry cognitions and values, hierarchical organizational structures, flexible institutional designs, and resource allocation strategies based on balancing risks and benefits collectively constitute the supporting system for megaproject collaborative innovation. At the macro level, the tight integration of the innovation chain and industrial chain promotes the formation of an open cooperation ecosystem, ensuring the continuity and systematic nature of innovation activities and accelerating the rapid commercialization and efficient utilization of innovation outcomes. This study not only enriches the theoretical connotations of IUR collaborative innovation in the context of major engineering projects but also provides theoretical foundations for strategy formulation and management practices for major project managers, holding significant value in guiding the innovation management of future major engineering projects.