Institutions in the United States are undergoing modifications that present direct challenges for the environment and society and may result in institutional uncertainty and instability. This article explores whether innovation intermediaries can be employed as a key component of a strategy to create a window of opportunity for green job creation, infrastructure changes, and technological innovation in response to these types of institutional modifications. Based on a systematic literature review, this article outlines a framework that combines institutional modifications with technological innovation and infrastructure development as part of an economic development strategy. Important findings are that connections between innovation intermediaries, such as incubator and accelerator centers, niche actors, such as green champions, and regime actors, such as policy entrepreneurs, show potential to contribute to a green economic development strategy but require further examination for the specific roles played by policy entrepreneurs to help create the conditions for scaling niche experiments and simultaneously disrupting the regime. The key contribution is in defining the role of sustainability-oriented innovation intermediaries at linking local, state and business actions in order to scale-up and influence green economic development in a politically feasible manner during times of institutional uncertainty and instability.