Purpose: The purpose of this paper is to illustrate and discuss the main features and key challenges of an original post-graduate education program designed according to an innovative theoretical framework promoting design thinking in a rhizomatic approach. By involving different stakeholders, the aim of this entrepreneurship education program is to disseminate rhizomatic, design-based learning competencies and thereby contribute to revitalizing a region's socio-economic fabric. Design/methodology/approach: Through the use of a pilot case, the paper exemplifies the application of the design thinking approach combined with the rhizomatic logic. Design thinking enables dealing with the complexity, uncertainty, and ill-defined problems that often characterize a business reality while the rhizomatic process combines the production of collective knowledge through a non-linear, complex and emergent path that nurtures innovation. Findings: This entrepreneurship education program exemplifies a viable strategy to deal with a regional economic crisis by engaging different local actors including enterprises, local institutions, municipalities, and universities. It demonstrates the potential value of a new educational approach as a powerful lever to activate the energy of people, their competencies, relationships, shared projects, and new entrepreneurial ventures. The first edition of the program offers ideas, practices, and challenges to all stakeholders of potentially similar education projects. Originality/value: The depicted pilot case allows us to exemplify how a design thinking framework reinterpreted on the basis of a Deleuzian rhizomatic perspective can enable developing innovation as a way of overcoming difficulties and succeeding, an essential prerequisite for many entrepreneurial organizations today.