<p indent=0mm>In response to the construction process of Healthy China, it is rather important to create a safe, healthy and energy-efficient indoor environment for public buildings. The public building space is often densely populated, with a large flow of people and many types of air pollution, which presents non-uniform dynamic distribution characteristics. This brings great challenges to the control of indoor air safety, especially during the pandemic period of COVID-19. Excessive ventilation may not only cause large energy waste, but also lead to cross-contamination and even cluster of infection. In this paper, an operation and maintenance (O&M) control system for indoor air safety is developed based on the core concepts and basic methods of human ergonomics. In this system, one of the important human environmental variables is focused for control, i.e., indoor air pollution level. Especially after the outbreak of COVID-19, droplets and droplet nuclei from respiration are the most significant air pollution categories required for mitigation. Towards the efficient control of air pollution in large public buildings, it should further take into account the interaction of human, equipment and machines (i.e., ventilation, air purification and disinfection and intelligent control system) and building environment. Firstly, on the basis of the online monitoring of indoor air pollution concentration and personnel flow, the non-uniform dynamic distribution of indoor pollutants and personnel can be obtained by using the non-uniform and low-dimensional rapid prediction models and computer vision processing. Then, the optimal setting results of ventilation parameters (e.g., ventilation modes, supply air rate, etc.) can be outputted by the environmental control decision system. Finally, based on a combination of monitoring sensors, controllers and actuator hardware equipment (at the location of fans or dampers), the intelligent regulation and control of ventilation system can be realized, aimed at minimizing energy consumption and reducing pollutant concentration and exposure level. Meanwhile, the air purification and disinfection system (especially for the disinfection of virus particles) are operated under the condition of the ventilated environment, which can serve as a powerful auxiliary to the maintenance of indoor air safety. The workflow and effect of the O&M control system are demonstrated by an engineering application case of the front hall in the International Convention and Exhibition Center. The results indicate that the non-uniform and low-dimensional rapid prediction model for pollutant concentration is effective for the ventilation control with the average prediction difference of 11.9%. The implementation of the intelligent ventilation system can reduce the risk of human infection to less than 4%, and its energy-saving ratio for the ventilation can be as high as about 45%. Through optimizing the layout strategies of disinfection devices based on the intelligent ventilation control, the space accessibility of negative oxygen ions can be well accepted, to further increase the removal efficiency of air pollution. The calculated value of space disinfection rate is more than 99%, which can further reduce the risk of infection by 1–2 orders of magnitude. This study can provide an important reference for the promotion and upgrading of O&M control system for indoor air safety.