Split-thickness skin grafting is a well-known procedure for the treatment of small- and medium-sized burns. However, its effectiveness has been reported to be limited in the case of large and severe burns due to much lower real expansion offered by the grafts than the claimed expansion by graft mesh manufacturers. Recent computational studies have indicated that the collagen fiber orientation within the skin layers have a significant effect on the skin graft expansion. In this study, biofidelic anisotropic synthetic skin with one and two layers and all possible fiber orientations were developed, and incision patterns used in traditional graft meshing techniques were projected to fabricate novel synthetic skin grafts with a theoretical meshing ratio of 3:1. A biaxial tensile testing device was designed to simulate skin graft stretching in clinical settings, and a wide range of synthetic skin graft variants were mechanically tested. The measured quantities included induced nonlinear stress–strain, void area, and meshing ratio. In addition, the stress–strain responses were characterized using nonlinear hyperelastic models. The key observations include the generation of higher induced stresses in two-layer grafts. In the one-layer graft models, a 15° fiber orientation produced the highest expansion at a minimal stress value of 0.21 MPa. In the two-layer graft models, the 45°–15° fiber orientation generated the maximum expansion with minimum stress. A range of such findings were analyzed to determine the graft orientations that may allow enhanced expansion without generating much stress. This information would be indispensable not only for understanding the expansion potential of skin grafts, but also for further research and the development of skin grafts with enhanced expansion for severe burn injury treatment.