The study provides an insight into the numerical strategies for describing the meso-scale mechanical response of running-bond masonry considering the variability of real masonry patterns. The approach proposes to model the masonry arrangement by using “test-windows” of different size and position for identifying the geometry of the micro-model that will be used for nonlinear analysis. The procedure has been applied to a literature experimental case of a wall under lateral loads, which has been modelled by assuming representative test-windows having different geometric ratios and positions. First, the in-plane response has been analyzed through non-linear static analysis and results for the different test-windows used are compared in terms of capacity curves, damage maps, and computation running time. Also, the yield domains of each arrangement under bi-axial stress conditions have been evaluated and compared. Finally, the orthotropy of the shear strength of the benchmark panel has been investigated in relation to the different test-window assumptions.