Multi-stage flash (MSF) desalination plays an important role in achieving large-scale fresh water driven by thermal energy. In this paper, based on first-principle modeling of a typical multi-stage flash desalination system, the effects of different operational parameters on system performance and operational optimization for cost saving were extensively studied. Firstly, the modelled desalination system was divided into flash chamber modules, brine heater modules, mixed modules and split modules, and based on energy and mass conservation laws the equations were formulated and put together to describe the whole process model. Then, with physical parameter calculation the whole process was simulated and analyzed on the platform of MATLAB, and the water production performance effected by operational parameters such as the feed temperature of seawater, the recycle brine from the discharge section, steam temperature and flowrate of recycled brine were discussed and analyzed. Then, the optimal operation to achieve maximize GOR (gained output ratio) with fixed freshwater demand was considered and performed, and thus the optimal flowrate of recycled brine, steam temperature, and seawater output flowrate from rejection section were obtained based on the established model. Finally, considering that minimizing the daily operational cost is a more rational objective, the operational cost equations were formulated and the optimal problem to minimize the daily operational cost was solved and the optimal manipulated variables at different hours were obtained. The study results can be used for guideline of real time optimization of the MSF system.