Due to hot arid climate in Jeddah, Saudi Arabia, occupants rely on air conditioning (AC) to provide both ventilation requirements and thermal comfort. It is believed that this total reliance on AC have also a significant effect on thermal sensation as well as cognitive performance of building occupants. Using a multi-variable multilevel statistical analysis, the effects of classroom temperature and CO2 levels on cognitive performance were estimated. Eight neurobehavioral cognitive tests were used to evaluate cognitive performance of 499 female students (16-20 years old). In addition, thermal sensation votes were collected. All participants were exposed to nine different environmental conditions, a combination of three temperature levels 20°C, 23°C and 25°C, and three CO2 levels: 600 ppm, 1000 ppm and 1800 ppm. The baseline condition levels were set at 20°C and 600 ppm. In this paper the interrelationships between the thermal sensation votes and effects of classroom temperature and CO2 levels on vigilance (Simple Reaction Test, SRT) and memory tasks (Reversal Learning, RL) are presented. The results suggested that the ‘cold’ thermal sensations have been linked to significant increase in ‘percentage of errors’ for both memory and vigilance tasks. Also, the exposure to higher CO2 levels of 1800 ppm and 1000 ppm have led to a significant increase in the ‘percentage of errors’ for both cognitive performance tasks compared to the baseline conditions. The study has also confirmed that the significant influence of acclimatization should not be overlooked when setting up the environmental design criteria for buildings in hot arid climates