Industry 4.0 promises better control of the overall product development process; however, there is a lack of computational frameworks that can inject human factors engineering principles early in the design. This shortage is particularly crucial for prototyping human-centered products where the stakes are high. Thus, a smooth Industry 4.0 transformation requires keeping ergonomics in the loop, specifically to address the needs in the digitized prototyping process. In this paper, we explore a computational prototyping approach that focuses on various fidelity levels and different human–product interaction levels when conducting ergonomics assessments. Three computational prototyping strategies were explored, including (1) a digital sketchpad-based tool, (2) computer-aided design and digital human modeling-based approach, and (3) a combination of computer-aided design, digital human modeling, and surrogate modeling. These strategies are applied to six case studies to perform various ergonomics assessments (reach, vision, and lower-back). The results from this study show that the designers need to consider the tradeoffs between the accuracy of ergonomic outcomes and resource availability when determining the fidelity level of prototypes. Understanding the intricacies between the fidelity level, type of ergonomic assessment, and human–product interaction level helps designers in getting one step closer to digitizing human-centered prototyping and meeting Industry 4.0 objectives.