Small and medium enterprises (SMEs) in the manufacturing industry normally arise as a result of product innovations. Transiting and growing into large organizations is a critical process for the sustainable growth of SMEs, and this requires developing appropriate production systems. Such development focuses on production economics and the optimization of facility layout, production capacity, and machine utilization. These optimizations are usually achieved using discrete event simulation (DES). However, the DES primarily focuses on production optimization and is not formulated to give concurrent attention to occupational health and safety risks, where the workers’ occupational health and safety are also important to production systems; hence, sustainability issues arise. Until now, the production economics and workers’ health and safety are usually treated separately, and the health and safety aspects are often managed after the system has been developed. This brings increasing hazards in the production environment since adding new facilities to the system may introduce new hazards and cause further safety issues. The present paper proposes a methodology to solve the above concerns. Its key features are the use of a quality-of-life metric for determining the occupational health and safety risks of a particular work activity and the embedding thereof as a routine in DES for manufacturing plant simulation. One of the contributions of the proposed integration method is that it helps to enhance the development of production systems that support financial due diligence, as well as occupational health and safety (OHS) due diligence. This is particularly important to SMEs in the manufacturing industries, where growth comes with particular sustainability challenges related to the need to develop more systematic operational and safety management systems.