This paper delves into the modifications to the main control room (MCR) layout within the context of an optimization project at a nuclear power station. Utilizing the foundational design of the MCR from the nuclear power station, a comprehensive and systematic design of the MCR’s air-conditioning system was undertaken, accompanied by a meticulous optimization of its ductwork layout. To ascertain the efficacy of the optimized ventilation, FLUENT fluid simulation software was employed, allowing for rigorous analyses of both the temperature and velocity fields. These analyses were conducted to rigorously validate the feasibility and effectiveness of the system. The results obtained reveal that within the operator’s working domain, the temperature is maintained within a range of approximately 20.6–22.2 °C, while the air velocity remains steady at around 0.16–0.21 m/s. This environmental control not only ensures the seamless operation of critical equipment but also aligns with the stringent comfort requirements for personnel within nuclear facilities. The findings of this research are not only pivotal for the ongoing optimization of existing nuclear power stations but also serve as an invaluable reference point for the design and engineering of future nuclear power projects. They reflect a deep understanding of the complexities involved in nuclear engineering and the importance of maintaining optimal environmental conditions within the MCR.