With the goal of decreasing the stress concentration along the hole boundary in an orthotropic plate under inequi-biaxial loadings, an optimum design of the fiber angle and hole orientation is presented. The maximum absolute tangential stress along the hole boundary is taken as the objective function, and the fiber orientation angle and the hole orientation angle are considered as design variables. The conformal transformation method of a complex function and the Differential Evolution (DE) algorithm are used. Two non-circular shapes, ellipse and hexagon are taken as examples to analyze the problem. Based on the results, we can conclude that the major axis of elliptical holes should be designed in the direction of the maximum external loading for a perforated structure in an orthotropic plate. However, the principal direction that has the larger Young’s modulus should be inclined to the direction of the minimum loading, especially for a significantly orthotropic plate.