Ergonomics has been playing an important role in assembly system design (ASD) that contains not only the main assembly line balancing problem but also the subassembly line balancing and assembly layout problem. The ergonomics in ASD has an impact both on productivity and on workers’ health, especially when frequent changes in the product mix occur. In this study, we propose a systematic approach in order to handle ASD, which consists of three subproblems, while considering ergonomic risk factors. The first two subproblems are solved simultaneously using the proposed rule‐based constructive search algorithm, where ergonomic risks are evaluated by OCRA method. Later, layout problem is solved under transportation constraints using local search methods with various neighborhood structures. To provide the applicability and evaluate the performance of the proposed systematic approach, a real‐life case study in a harness manufacturing company is solved and prototype productions are performed.