Closed-loop control system of greenhouse temperature was established for multi-index optimization by CFD modeling. In the system, multi-index including average temperature, temperature distributed and control cost, and control scene was natural ventilation. In order to minimize these indexes under the control mode, the GA optimization algorithm was adopted to obtain the optimal control outputs (entrances and skylights amplitudes). Simulation experiment shows that the technique of CFD for model can hold whole greenhouse environment into one system to improve control accuracy, and the control objective by CFD model is a “field”, not a “point” as tradition. Meanwhile, using GA algorithm can get the optimal control inputs in multi-index system for reducing regional difference and energy consumption synchronous, so this design technique can richen the technology in greenhouse control system.