In the era of Industry 4.0, human-machine systems have become highly complex and contain a large number of elements and sources of information. It increases the complexity of human-machine system management, which leads to the manifestation of the human factor phenomenon. The consequence is that currently, 70% to 90% of accidents and disasters are related to the human factor. Therefore, the safety of human-machine systems largely depends on human abilities, cognitive, behavioral, and psycho-physiological features. It is shown that the study of individual characteristics of a person will allow the management of the human factor in the human-machine system. The crucial point of human factor management is the availability of systemic ergonomic thinking in the designer of the human-machine system. The formation of such thinking is connected with learning and the gradual acquisition of the necessary knowledge and skills. To understand the principles of ergonomic thinking formation, the evolution of ergonomic thinking in the design of human-machine systems is shown. Due to analysis of the sequence of ergonomic thought development, it is shown how approaches to ensuring the safety of human-machine systems have been rethought from the middle of the 20th century until now. Currently, the global social processes and technologies of Industry 4.0 have fundamentally changed the concept of “work”, parameters of the labour market, and safety requirements and caused the emergence of a new model of the labour paradigm “Work 4.0”, which, in turn, became the driver of the revision of the concept of “workplace” established in society and the emergence of the digital workplace. The article presents the definition of a “digital workplace” and analyses its essential characteristics. The next stage of the work was a model of the structure of the engineer’s ergonomic thinking, the main feature of which is the priority of solving the problems of human-machine interaction. The work also shows that ergonomic thinking is one of the elements of safety culture. In combination with other elements such as a human-centered approach, ecological thinking and others, ergonomic thinking creates a space of a safety culture. Based on the presented results, the importance of engineers’ ergonomic thinking is substantiated. It is shown how to implement the formation of ergonomic thinking through the training system.