Buildings are responsible for almost half of the world’s energy consumption, and approximately 40% of total building energy is consumed by the heating ventilation and air conditioning (HVAC) system. The inability of traditional HVAC controllers to respond to sudden changes in occupancy and environmental conditions makes them energy inefficient. Despite the oversimplified building thermal response models and inexact occupancy sensors of traditional building automation systems, investigations into a more efficient and effective sensor-free control mechanism have remained entirely inadequate. This study aims to develop an artificial intelligence (AI)-based occupant-centric HVAC control mechanism for cooling that continually improves its knowledge to increase energy efficiency in a multi-zone commercial building. The study is carried out using two-year occupancy and environmental conditions data of a shopping mall in Istanbul, Turkey. The research model consists of three steps: prediction of hourly occupancy, development of a new HVAC control mechanism, and comparison of the traditional and AI-based control systems via simulation. After determining the attributions for occupancy in the mall, hourly occupancy prediction is made using real data and an artificial neural network (ANN). A sensor-free HVAC control algorithm is developed with the help of occupancy data obtained from the previous stage, building characteristics, and real-time weather forecast information. Finally, a comparison of traditional and AI-based HVAC control mechanisms is performed using IDA Indoor Climate and Energy (ICE) simulation software. The results show that applying AI for HVAC operation achieves savings of a minimum of 10% energy consumption while providing a better thermal comfort level to occupants. The findings of this study demonstrate that the proposed approach can be a very advantageous tool for sustainable development and also used as a standalone control mechanism as it improves.