The mechanical response of bio-inspired irregular sutural tessellations with Voronoi tile patterns are designed and fabricated via multi-material 3D printing. The effective mechanical properties of the designs were characterized via uni-axial tension mechanical experiments on the 3D printed specimens. Systematic nonlinear finite element simulations are conducted to explore the damage initiation and evolution of the designs. The influences of important design parameters, including tile length aspect ratio R, tile size irregularity Cstd, suture amplitude irregularity Astd, and stiffness ratio between the soft and hard phases, were evaluated. The effective stiffness, Poisson’s ratio, strength, toughness, and failure mechanisms are systematically quantified. The results demonstrate that an optimized level of suture irregularity exists for maximizing the modulus of toughness. The results provide a general design guideline for designing functionally graded two-phase tessellations with high mechanical performance.