The validation of structural health monitoring (SHM) systems for aircraft is complicated by the extent and number of factors that the SHM system must demonstrate for robust performance. Therefore, a time- and cost-efficient method for examining all of the sensitive factors must be conducted. In this paper, we demonstrate the utility of using the simulation modeling environment to determine the SHM sensitive factors that must be considered for subsequent experiments, in order to enable the SHM validation. We demonstrate this concept by examining the effect of SHM system configuration and flaw characteristics on the response of a signal from a known piezoelectric wafer active sensor (PWAS) in an aluminum plate, using simulation models of a particular hot spot. We derive the signal responses mathematically and through the statistical design of experiments, we determine the significant factors that affect the damage indices that are computed from the signal, using only half the number of runs that are normally required. We determine that the transmitter angle is the largest source of variation for the damage indices that are considered, followed by signal frequency and transmitter distance to the hot spot. These results demonstrate that the use of efficient statistical design and simulation may enable a cost- and time-efficient sequential approach to quantifying sensitive SHM factors and system validation.