Increasing volatility and product individualization are leading to higher complexity in manual assembly. At the same time, production and processes must become more flexible, and humans have to adapt to new products more often and even faster. Industry 5.0 will increasingly focus on human-centric approaches, on the collaboration of humans and machines intensively using cognitive assistance systems. The design of an innovative cognitive assistance system is a complex task due to the many technological opportunities and their interrelationships. In the framework of this research, a method was developed enabling the systematic design of cognitive assistance systems that integrates business and worker requirements aiming at improving productivity, quality, worker satisfaction and well-being. The research question was approached by design science research having, as the main output, a systematic and innovative method for the design of cognitive assistance systems based on quality function deployment (QFD), referred to as cognitive assistance system-QFD (CAS-QFD). The developed methodology is divided into six phases and includes the iterative design of a cognitive assistance system starting from the assembly process. The method considers the information needs of the workers, the definition of the appropriate assistance functions and the selection of the interaction technologies. The exemplarily industrial evaluation highlighted the relevance of CAS-QFD for systematically designing cognitive assistance systems based on holistic requirements, identified at the worker, workplace, production area and, finally, at the enterprise level.