In recent years, there has been debate about the reliability of the results obtained from thermal-energy simulations of buildings, specifically about the so-called performance gap, or difference in behavior between the real and the simulated. The validation of simulation models of ventilation and thermal systems of an archetypical school classroom in a Mediterranean climate in southern Spain is the main objective of this work. For this purpose, first, hygrothermal and air quality variables have been monitored in situ in this classroom, with different ventilation and thermal treatment systems; virtual models have been generated with TRNSYS and, finally, the models have been adjusted and validated. The ventilation and thermal systems analyzed were: (1) Natural ventilation combined with heating by radiators, the most common solution in southern Spain; (2) mechanical ventilation combined with heating by radiators in winter or with adiabatic cooling in summer, a novel efficient solution that educational authorities are promoting to mitigate the increasingly frequent overheating of classrooms. The results for validated models show low discrepancies between measured and simulated, with average tolerances between 0.3 and 1 °C for temperature and between 32.8 and 106.4 ppm for CO₂. These error margins comply with the standards and are acceptable for a study of indoor environmental conditions. These models enable the suitability assessment of various energy retrofitting options to address future climate change challenges, not only regarding the building’s thermal envelope but also its HVAC systems.