Abstract: It is a determined measure to promote the innovation strategy of science and technology and cope with the current development challenges to construct a reasonable development plan and an efficient operative mechanism of the national innovation system of systems centering on national laboratories. This paper focuses on the Virtual National Laboratory (VNL) of the US. With this case analysis, the development path and the management model of the VNL are studied. Moreover, the development and the application of high-tech projects, the characteristics of the collaborative innovation operative mechanism are reviewed, including an organic combination of the government coordination and the market operation, the extensive participation of various powers, the effective protection for the intellectual property of innovation achievements, and the efficient information communication mechanism. Finally, related suggestions are proposed, as well as the enlightenments of the VNL and the existing management problems of Chinese major scientific research institutions. Firstly, the innovation mechanism for compound scientific research projects should be explored, which combines the government coordination and the market demands. Secondly, the administration should give full play to the cohesive function of national laboratories to enhance the basic scientific research leveraging industry power. Thirdly, the agile response mechanism of scientific research requirements should be constructed quickly for interdisciplinary and comprehensive projects with multiple stake-owners.