<p>Government-industry-university-institute (GIUI) collaborative innovation is widely acknowledged as a core driver of innovation-driven growth. However, many collaborations remain superficial due to fragmented resource allocation and misaligned incentives. This paper adopts an exploratory case study approach to analyze successful cases from South China University of Technology, proposes the strategic-organizational-knowledge synergy framework, applies evolutionary game theory to construct a tripartite evolutionary game model involving government, industry, universities, and institutes, and simulates the impact of strategic, organizational, and knowledge-based elements on collaborative innovation. The findings reveal that the strategic synergy mechanism serves as the foundation for GIUI collaborative innovation, organizational synergy provides structural support, and knowledge synergy acts as the critical enabler. The deep integration and sustainable development of GIUI collaborative innovation rely on the coordinated input of strategic, organizational, and knowledge-based elements, as well as comprehensive system-level contributions.</p>