Engineering 4.0 environments are characterised by the digitisation, virtualisation, and connectivity of products, processes, and facilities composed of reconfigurable and adaptive socio-technical cyber-physical manufacturing systems (SCMS), in which Operator 4.0 works in real time in VUCA (volatile, uncertain, complex and ambiguous) contexts and markets. This situation gives rise to the interest in developing a framework for the conception of SCMS that allows the integration of the human factor, management, training, and development of the competencies of Operator 4.0 as fundamental aspects of the aforementioned system. The present paper is focused on answering how to conceive the adaptive manufacturing systems of Industry 4.0 through the operation, growth, and development of human talent in VUCA contexts. With this objective, exploratory research is carried, out whose contribution is specified in a framework called Design for the Human Factor in Industry 4.0 (DfHFinI4.0). From among the conceptual frameworks employed therein, the connectivist paradigm, Ashby’s law of requisite variety and Vigotsky’s activity theory are taken into consideration, in order to enable the affective-cognitive and timeless integration of the human factor within the SCMS. DfHFinI4.0 can be integrated into the life cycle engineering of the enterprise reference architectures, thereby obtaining manufacturing systems for Industry 4.0 focused on the human factor. The suggested framework is illustrated as a case study for the Purdue Enterprise Reference Architecture (PERA) methodology, which transforms it into PERA 4.0.