PurposeThis paper proposes adequate strategies that companies, public administrators and organisations in the education industry can undertake to successfully face the challenges of digital transformation in a regional innovation system. This research considers stakeholders that operate in the Tyrol–Veneto macroregion (the Tyrol, South Tyrol and Veneto areas), a significant case of moderately innovative European macroregion.Design/methodology/approachThis study undertakes explorative research based on a qualitative method. It adopts a place-based multi-stakeholder approach to emphasise the role of three categories of stakeholders (companies, educational system and regional governments) in facing digital changes. More precisely, interviews with 60 stakeholders from the Tyrol–Veneto macroregion were conducted and examined via both text mining analysis and content analysis. First, correspondence factor analysis was performed using IRaMuTeQ software to identify homogeneous subsets of concepts (pillars–i.e., macroareas of strategic actions). Second, two coding phases were implemented using NVivo software to detect strategic fields of action and specific strategic actions undertaken to address the challenges of digital transformation.FindingsThe results highlight that digital transformation is a pervasive challenge of regional innovative system that requires a multifaceted set of strategic actions falling into three main pillars. The first pillar, named “culture and skills”, includes three strategic fields of action as follows: digital education, talents and digital culture. The second pillar, named “infrastructures and technologies”, points out the need of information, interaction and artificial intelligence as key strategic fields of action. The third pillar, named “ecosystems”, highlights the importance of investing in medium- to long-term visions, partnerships and life quality. In brief, this study shows that standalone interventions are insufficient to tackle digital transformation from a systemic perspective. Moreover, this study outlines the potential contribution of each category of stakeholder to foster the digitalisation of the Tyrol–Veneto macroregion.Practical implicationsThis study highlights the importance of developing digital culture and skills before investing in digital infrastructure and technology in a moderately innovative macroregion. Companies should alter their vision before reconfiguring their business models, invest in smart working and establish contacts with start-ups. In addition, this study recommends that public administration should mainly invest in digital education and partnerships, while, in terms of education and training organisations, it suggests providing digital skills to several cohorts of both students and workers. Policy implications call for the creation of new occasions of cooperation among stakeholders by fostering “table talks” as strategic and policy actions and by making more financial resources available to encourage the digital transformation processes.Originality/valueThe results of this study may be adapted to the characteristics of other regional innovative systems and used as a reference point in terms of the improvement of business, market and local development.