This paper presents a manifesto for the future design of human-made systems and engage this reflection by promoting a computational human factors engineering (HFE) approach. In this paper, we concentrate on the fact that human well-being and sustainability objectives are inseparable. Thus, this paper’s primary focus is to demonstrate a simulation-based computational design methodology, digital human-in-the-loop (D-HIL), which utilizes the digital human modeling (DHM) platform to inject HFE design principles early in design. The D-HIL methodology enables human, product, and systems data to be coupled with computational toolkits; thus, bringing opportunities for facilitating ergonomics decision-making to be part of the digital twin (DT)-driven design. We presented two frameworks originating from our recent work in D-HIL research: (1) prototyping toolbox and (2) human error and functional failure reasoning (HEFFR) as means for realizing sustainability goals through DT-based design. While our preliminary studies show that both tools show promise in terms of realizing the sustainability goals, they are limited to only goals that relate to cost. In our future work, we plan to explore models and computational tools from non-traditional engineering domains to expand our frameworks’ scope to realizing sustainability goals that go beyond cost estimations.