Because of the global competition of greenhouses and the importance of the global food safety, designing higher yield and efficiency greenhouse systems becomes a hot spot problem. A greenhouse designed for industrial head lettuce production not only can increase yield by using A-Frame systems, but can also improve efficiency through an operation process of alleviating human labor by machines. However, the facility layout problem (FLP) of greenhouse with complex crop production system and multi machines was always ignored in the past decades. In order to maximize production capacity and efficiency, the FLP of greenhouse should be considered as an essential section at the conceptual design phase. To overcome these problems, a framework integrating systematic layout planning (SLP) and simulation is proposed to design and evaluate facility layout in greenhouses. When applying the framework to the facility layout for industrial head lettuce production, we can get the optimal layout plan which lead to a daily production of 7752 head lettuces within about 98 min in a greenhouse of 14,784 m² and an efficiency improvement of 67.31% compared with another initial layout plan. These research results can help the designer find a more effective layout and the managers to support decisions before greenhouse construction.