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The innovation-driven Industry 5.0 leads us to consider humanity in a prominent position as the center of the manufacturing field even more than Industry 4.0. This pushes us towards the hybridization of manufacturing plants promoting a full collaboration between humans and robots. However, there are currently very few workplaces where effective Human–Robot Collaboration takes place. Layout designing plays a key role in assuring safe and efficient Human–Robot Collaboration. The layout design, especially in the context of collaborative robotics, is a complex problem to face, since it is related to safety, ergonomics, and productivity aspects. In the current work, a Knowledge-Based Approach (KBA) is adopted to face the complexity of the layout design problem. The framework resulting from the KBA allows for developing a modeling paradigm that enables us to define a streamlined approach for the layout design. The proposed approach allows for placing resource within the workplace according to a defined optimization criterion, and also ensures compliance with various standards. This approach is applied to an industrial case study in order to prove its feasibility. A what-if analysis is performed by applying the proposed approach. Changing three control factors (i.e., minimum distance, robot speed, logistic space configuration) on three levels, in a Design of Experiments, 27 layout configurations of the same workplace are generated. Consequently, the inputs that most affect the layout design are identified by means of an Analysis of Variance (ANOVA). The results show that only one layout is eligible to be the best configuration, and only two out …