Several studies found that classrooms' indoor environmental quality (IEQ) can positively influence in-class activities. Understanding and quantifying the combined effect of four indoor environmental parameters, namely indoor air quality and thermal, acoustic, and lighting conditions on people is essential to create an optimal IEQ. Accordingly, a systematic approach was developed to study the effect of multiple IEQ parameters simultaneously. Methods for measuring the IEQ and students' perceived IEQ, internal responses, and academic performance were derived from literature. Next, this systematic approach was tested in a pilot study during a regular academic course. The perceptions, internal responses, and short-term academic performance of participating students (n = 163) were measured. During the pilot study, the IEQ of the classrooms varied slightly. Significant associations (p < 0.05) were observed between these natural variations and students' perceptions of the thermal environment and indoor air quality. These perceptions were significantly associated with their physiological and cognitive responses (p < 0.05). Furthermore, students' perceived cognitive responses were associated with their short-term academic performance (p < 0.01). The observed associations confirm the construct validity of the systematic approach. However, its validity for investigating the influence of lighting remains to be determined.