Purpose The purpose of this paper is to statistically assess the effects of the design factors including usage of data-driven decision support tool (DST), classification of patients (triage), prioritization based on vital scores of patients, number of ambulances and hospital selection rules, on the casualty transportation system's performance in large-scale disasters. Besides, a data-driven DST for casualty transportation is proposed to enhance the casualty survival and ambulance transportation times during the disaster response stage. Design/methodology/approach In this study, the authors applied simulation and statistical analysis to evaluate the effects of usage of data-driven DST, classification of patients (triage), prioritization of the patients based on vital scores, number of ambulances and hospital selection rules, on the patient survival and transportation time of the casualty transportation system. An experimental design was made, and 16 scenarios were formulated. Simulation models were developed for all scenarios. The number of unrecoverable casualties and time-spent by the casualties until arriving at the hospital was observed. Then, a statistical analysis was applied to the simulation results, and significant factors were determined. Findings Utilization of the proposed DST was found to improve the casualty transportation and coordination performance. All main effects of the design factors were found statistically significant for the number of unrecoverable casualties. Besides, for the Time spent Until Arrival of T1-Type Casualty at the Hospital, all of the main factors are significant except the number of ambulances. Respiratory rate, pulse rate, motor response score priority and hospital selection rule based on available hospital capacities must be considered to reduce the number of unrecoverable casualties and time spent until arrival of the casualties at the hospitals. Originality/value In this study, the factors that significantly affect the performance of the casualty transportation system were revealed, by simulation and statistical analysis, based on an expected earthquake case, in a metropolitan city. Besides, it was shown that using a data-driven DST that tracks victims and intends to support disaster coordination centers and medical staff performing casualty transportation significantly improves survival rate of the victims and time to deliver the casualties. This research considers the whole systems' components, contributes to developing the response stage operations by filling gaps between using the data-driven DST and casualty transportation processes.