Recent years have seen rapid changes in the workplace arising from the digital and green transitions (‘twin transition’), as well as the COVID-19 pandemic. New forms of work and work management have arisen, which can affect the physical and mental health of workers in new ways (both positive and negative) that are not yet well understood. Yet, workplaces can be health-promoting environments. Robust, comprehensive data must be generated, made available to key stakeholders, translated into evidence-based guidance to support the design of policies and used to develop evidence-based interventions and guidelines to promote mental and physical well-being and health in the workplace. PROSPERH will gather timely data and robust evidence on factors influencing mental and physical health in the workplace from the literature and analysis of existing high-quality datasets. Based on this evidence and building on existing EU-funded and national interventions, the project will develop and validate the multi-level PROSPERH intervention, delivered via the PROSPERH Portal. The intervention will target both organisational (work), peer and individual (worker) aspects, with three components focusing on health promotion, online self-monitoring & self-management and clinical care or coaching referral pathways. Development will focus on tailoring content for three sectors experiencing significant change (telework and ICT-based mobile work, health and construction), with validation carried out in 10 representative European countries and Australia through a cluster-randomised controlled trial to determine effectiveness and cost-effectiveness. To ensure that the expected impacts of PROSPERH are achieved during and beyond the project lifetime, key outputs of the project will include open access publications and FAIR datasets, guidelines and recommendations and a roadmap for making the PROSPERH Portal freely available in a sustainable manner.