When decommissioning a nuclear power plant, a large amount of radioactive waste is generated simultaneously. Therefore, efficient treatment of radioactive waste is crucial to the success of the decommissioning process. An utility or decommissioning contractor of NPP often build separate radioactive waste treatment facilities (RWTF) to handle this waste. In Korea, RWTFs are planned to be built for the decommissioning of the Kori Unit 1 and Wolsong Unit 1. In this study, we introduce an application case of using process simulation to derive the optimal layout design and investment plan for a radioactive waste treatment facility. In particular, the steam generator is the largest and most complex device processed in RWTF. Therefore, it is necessary to reflect the large equipment processing area that can treat steam generators in the design of RWTF. In this study, Siemens’ Plant Simulation® was used to derive an optimization plan for the dismantling area of large equipment in RWTF. First, a virtual facility was built by modeling based on the steam generator dismantling process and facilities developed by Doosan Enerbility. This was used to pre-validate the facility investment plan, discover wasteful factors in the logistics waste streams, and evaluate alternatives to derive, validate, and apply appropriate improvement alternatives. Through this, we designed a layout based on the optimal logistics waste streams, appropriate workstations, and the number of buffer places. In addition, we propose various optimization measures such as investment optimization based on optimal operation of facility resources such as facilities and manpower, and establishment of work standards.