Due to the long-term summer in southern China, the crops in greenhouses suffer from high temperature seriously. In order to improve the cooling effect and reduce the energy consumption of ventilation, it is necessary to optimize the design and control strategy for the mechanical ventilation system of greenhouses. A full-scale 3-D transient and steady CFD simulation model was established for a typical multi-span plastic greenhouse in southern China. By using evenly distributed temperature, humidity and light sensors inside and outside the greenhouse, the variation and distribution of temperature driven by the mechanical ventilation were measured. The comparison between the experimental and simulation results showed that the CFD model was valid. Under the high ambient temperature, the CFD model was carried out to investigate the impact of design parameters, such as the number of working fans, length of greenhouse, inlet temperature and outside environment temperature, on cooling effect of mechanical ventilation. And then the cooling effect under different control strategies of mechanical ventilation was simulated to reduce the energy consumption. The proposed CFD model can provide optimized parameters for the design and control of multi-span plastic greenhouse mechanical ventilation in summer, which can be applied to improve the cooling effect and reduce energy consumption of ventilation.