This paper focuses on the application of an innovative numerical approach to assessing the nonlinear dynamic response of an unstrengthened masonry cross vault subjected to shaking table testing performed within a blind prediction context. The numerical approach corresponds to the Discrete Macro-Element Method (DMEM), which consists of the assemblage of 2D panels and allows the assessment of the main in-plane and out-of-plane mechanisms of masonry structures according to a simplified mechanical scheme. A sensitivity analysis was carried out to determine the influence of the linear and nonlinear properties on the seismic response of the unstrengthened masonry cross vault. The calibration of the numerical model allowed reasonable agreement between experimental and numerical dynamic properties (natural frequencies and mode shapes). In addition, the numerical model provided acceptable results in terms of history of displacement and collapse mechanisms due to the application of nonlinear dynamic analyses. The results presented in this paper demonstrate the applicability of a simplified numerical method for assessing the seismic response of complex structures.