In the industrial field, one of the most widespread KPIs is represented by the Overall Equipment Effectiveness (OEE), first introduced by Seiichi Nakajima within the Total Productive Maintenance (TPM) theory and aimed at identifying the inefficiencies of industrial assets. While OEE has been objective of several studies, the relationship between the Overall Equipment Effectiveness and the role of the human factor in achieving its high levels of values has not been extensively investigated. In recent years few scientific studies have investigated the relationship, showing that there is a link between OEE and human factors, even significant, but not clearly identified yet. In order to examine this relationship, our study proposes a framework to clarify the links between human factors, OEE parameters, the industrial sector, and the degree of automation. This framework is then validated through the application of the Analytic Hierarchy Process (AHP) methodology. As a result, 13 aspects related to the human factor were identified. Finally, the study provides practical guidance and implications for maximizing the outcomes of the investigation, with the goal of improving an organization’s overall manufacturing performance. By understanding the impact of the human factor on OEE, organizations can make informed decisions to optimize their operations and achieve higher levels of productivity.