Due to the shift from mainly manual labor to an increased portion of cognitive tasks in manufacturing caused by the introduction of cyber-physical systems, there is a need for an updated collection of adequate design principles for user interfaces between humans and machines. Thus, we developed a method for the determination and evaluation of such design principles. It is based on human factors methods and facilitates the assessment of specific work design elements which are supposed to have a significant effect on work performance and the perception of work in cyber-physical production systems (CPPS). Within the application of the developed method, we derived an overview of key design elements in CPPS, developed an experimental platform, and conducted two empirical studies with a total of n = 68 participants. This way, three design elements were investigated, and the findings transferred into preliminary design principles. We can state that the method can be used both for a better understanding of the mechanisms between human factors and work in CPPS. Besides, it helps to provide a catalogue of design principles applicable to SMEs to promote more efficient and successful integration of workers into CPPS.