This paper presents numerical investigations using the mesoscale approach coupled with the discrete macro-element approach for masonry structures, i.e., each macro-element represents a single unit stone. At first, parametric analyses are performed on a U-shape masonry prototype made with stone. Nonlinear static analyses are performed to investigate parameters that affect the results when a mesoscale masonry pattern representation is adopted. Results demonstrate how mesoscale representation is a powerful alternative to model unreinforced masonry structures within a discrete macro-element approach (particularly if compared with classic homogeneous FE methodologies). However, one of the main challenges in using the mesoscale approach for the structural assessment of masonry buildings, made with stones having different dimensions, is the unit by unit description. The complexity of the problem, and the amount of information needed, usually preclude the study of these structures deterministically. To this end, a digital tool to generate randomised masonry patterns using a few input parameters is proposed. A box structure is adopted as parent geometry, and ten masonry patterns with different degrees of randomness are investigated by performing nonlinear static and dynamic simulations. The outcomes focus on the influence of masonry patterns and demonstrate how irregularity of units can affect the structural response leading to a reduction in terms of strength and ductility if compared to regular distribution of masonry units.