Several masonry structures of cultural and historical interest are made with a non-periodic masonry material. In the case of periodic textures, several methods are available to estimate the strength of the masonry; however, in the case of non-periodic masonry, few methods are available, and they are frequently difficult to use. In the present paper we propose using discontinuity layout optimization (DLO) to estimate the failure load and mechanism of a masonry wall made with non-periodic texture. We developed a parametric analysis to account for the main features involved in the estimation of failure: in particular we considered three different textures (periodic, quasi-periodic, and chaotic), variable height-to-width ratio of the wall (from 0 to 3) and of the blocks (from 0.25 to 1), different mechanical properties of mortar joints and blocks, and possible presence of a load on the top. The results highlight the importance of the parameters considered in the analysis, both on the values of the failure load and on the failure mechanism. Therefore, it is found that DLO can be an useful and affordable method in order to assess the mechanical strength of masonry wall made with non-periodic textures.