Energy modeling is a key tool for improving energy efficiency in greenhouse horticulture, where climate control directly affects crop growth and productivity. Unlike other built environments, greenhouses require dedicated modeling approaches due to their sensitivity to external climate, crop transpiration, and seasonal dynamics. In this study, the energy model of a one-span greenhouse located in a Mediterranean climate was developed using EnergyPlus with the OpenStudio interface, a ready-to-use tool for energy simulation. The model results were compared with monitored data. Given the complexity of the greenhouse environment and the presence of numerous independent variable factors, a calibration step was performed to align the model’s predictions with measured data, ensuring an accurate representation of the greenhouse. The results were analyzed using statistical indexes. The Root Mean Square Error for indoor air temperature was 1.52 °C, which indicates the model is sufficiently accurate and can serve as a reliable basis for future research aimed at reducing greenhouse energy consumption and increasing horticultural productivity. Potential applications include the creation of a digital twin model for greenhouse environments and the integration of additional factors such as carbon fertilization. Moreover, the study highlights the key parameters that most significantly influence energy simulation outcomes, providing valuable insights for further optimization.