The need for production of all kinds of crops in high quantities and over the entire year makes the agricultural sector one of the major energy consumers. The optimization of this consumption is essential to guarantee its sustainability. The implementation of greenhouses is a strategy that allows assurance of production needs and possesses large optimization potential for the process. This article studies different greenhouse structures by computational simulation using EnergyPlus and DesignBuilder. First, a comparison was performed between the computational results and the measured values from a greenhouse prototype at different operating conditions. Overall, the comparison shows that the computational tool can provide a reasonable prediction of the greenhouse thermal behavior, depending on the differences between the weather data modeled and observed. An outdoor air temperature difference of 16 °C can cause a difference of about 10 °C between the air temperature predicted and measured inside the greenhouse. Subsequently, a selected set of case studies was developed in order to quantify their influence on the thermal performance of the greenhouse, namely: the greenhouse configuration and orientation; the variation of indoor air renewal; changes to the characteristics of the roof; the effect of the thermal mass of the walls; and location of the greenhouse. The results show that a correct greenhouse orientation, together with a polyethylene double cover with a 13 mm air layer, a granite wall of 40 cm thickness on the north wall, and variable airflow rate, may lead to a reduction of the greenhouse energy consumption by 57%, if the greenhouse is located in Lisbon, or by 43%, if it is located in Ostersund, during the harshest months of the heating season.