The advent of modern digital technologies offers new opportunities to improve the performance of manufacturing systems from design to monitoring and control during operation. At the same time, the recent COVID-19 pandemic has highlighted the fragility of all global supply chains and manufacturing systems. In this paper, a simulation-based framework, exploiting the benefits of the digital model concept, is proposed. It aims at: (1) supporting manufacturing design to effectively start a new business, (2) assessing the resilience of a manufacturing system in the face of disruptions, (3) evaluating the goodness of possible strategies to deal with COVID-like crises. The validity of the proposed framework is successfully demonstrated through a real-life case study, referring to the wood sector. The results show that a lack of system preparedness can lead to productivity reductions of up to 31.8%. At the same time, having the ability to react to unexpected events can limit damage and increase productivity by 26% compared to not reacting.