The fourth industrial revolution (I4.0) is driving the development of automated and intelligent manufacturing systems, but managing these systems poses challenges, especially for maintenance and process control. The emerging Industry 5.0 (I5.0) concept advocates for a human-centered approach, integrating human skills with advanced technologies to address such challenges. This study introduces a novel holistic evaluation of ergonomics, moving beyond traditional physical assessments to include cognitive ergonomics, thus providing a more comprehensive analysis of operator interactions with industrial systems. The proposed approach leverages Virtual Reality (VR) simulations combined with wearable devices to collect data on users’ movements and physiological parameters. This enables simultaneous evaluation of physical workload and cognitive demands, fostering early identification of ergonomic issues in the design process. Unlike traditional methods, our framework emphasizes a deeper integration of devices for enhanced data analysis, ensuring that both physical and cognitive factors are addressed. As a case study, the redesign of an automated packaging machine was undertaken. Results demonstrated significant ergonomic improvements, reducing the EAWS (European Assessment Work-Sheet) score (from 30% to 50% approx.) and incorporating cognitive ergonomics into the evaluation. These findings highlight the potential of this approach to enhance the operator’s experience and optimize human-machine interaction in modern industrial environments.