Small and Medium Enterprises (SMEs) in Central Europe, particularly manufacturing companies, face significant challenges due to technological advancement, digitalization, climate change, and demographic shifts. To address these challenges, there is a growing need for effective strategies that support SMEs in transitioning toward sustainable and resilient business models within the context of Industry 4.0. The paper highlights the importance of SMEs adopting new concepts like innovation culture, digital manufacturing, open innovation and circular economy. However, many manufacturing SMEs in Central Europe lack the necessary capacities, including know-how, human capital, and organizational and managerial capacity, to effectively adopt these new concepts and models. In response, the SME Ready for the Future (SMERF) project proposes a comprehensive approach to support manufacturing SMEs in Central Europe through the implementation of tailored support mechanisms. This paper presents the development of the SMERF concept and methodology, which focuses on four pillars: Innovation Culture, Digital Manufacturing, Open Innovation & Sharing Economy, and Green & Circular Economy & Sustainability. The methodology aims to assess SMEs’ levels of advancement and provide transformation scenarios, fostering economic growth, innovation, and sustainability in the region. Through the SMERF project, manufacturing SMEs will be empowered to thrive in Industry 4.0 by embracing open innovation and technology transfer models for sustainable manufacturing.