The current global environmental situation, with its interconnected problems, requires holistic approaches to provide a cultural paradigm shift and a different economy to overcome the linear one. Systemic Design (SD) can represent a solution creating opportunities for eco- and system innovation, especially in the manufacturing sector, which will soon face a revolution in the production model. Thus, SD can help achieve environmental and economic sustainability at the local level. A multiple case study analysis on SD projects was developed to understand the significant eco-entrepreneurial opportunities that have emerged and the barriers for their implementation. Finally, an ecosystem is designed to foster systemic innovation based on helix innovation models and identify the facilitator for its creation, namely, the ‘local systemic network booster’.