Emergency ventilation plays an important role in protecting occupants when a hazardous contaminant is released indoors. A number of studies have been conducted to better understand how to protect indoor occupants with effective ventilation strategies. However, little attention has been paid to the impact of the non-uniform and time-dependent distribution of occupants during evacuation. A new concept, Efficiency Factor of Contaminant Source (EFCS), has recently been proposed to evaluate the performance of emergency ventilation by comprehensively considering the spatial and temporal distributions of both the contaminant and occupants. This paper aims to: (1) propose and demonstrate a procedure for determining an optimal ventilation strategy by using EFCS; (2) examine the effects of source locations, ventilation modes, and evacuation modes on the performance of emergency ventilation. One hundred cases with ten ventilation modes, two evacuation modes, and five source locations were investigated numerically. The results show that the EFCS concept can provide a reasonable way to evaluate the performance of emergency ventilation. The threats of different source locations may vary over a large range, and certain measures should be taken to monitor and prevent the releases at high threat locations. A system equipped with multiple ventilation modes is necessary since no universal ventilation mode can successfully mitigate all hazardous situations. The effects of an evacuation mode may be more significant than that of a ventilation mode under certain situations.