Aircraft cargo compartment fires are one of the main threats to the safety of civil aircraft. In this study, a series of numerical simulations on the fire suppression performance of water mist in cargo compartments was carried out to examine the effects of the spray pattern, droplet size, and nozzle layout. The fire dynamics simulator (FDS) code was used to construct a fire suppression scenario in a full-scale aircraft cargo compartment. The results show that the extinguishment time of a corner fire was longer compared with center and sidewall fires due to the relatively larger distance from the nozzle and, therefore, a lower effective number of droplets reaching the flame area. Solid and hollow spray patterns showed significant differences in the spray coverage area. For a fixed flow rate, the hollow spray showed better fire suppression performance than solid spray. When the droplet size varied from 50 to 400 µm, the fire extinguishment time first increased and then decreased, corresponding to the dominant mechanism of the smothering effect of small droplets and the cooling effect of large droplets. In addition, the nozzle layout affected the water coverage on the ground of the cargo compartment. With an increase in nozzle number, the water mist flux was more evenly distributed and the fire extinguishment effect also increased.