This paper proposes design optimization of a mechanically decoupled six-axis F/T sensor. In order to indicate the biggest cross coupling error of a Maltese cross type F/T six-axis sensor, principal error is proposed in this paper. Locations of twenty-four strain gages are determined and four design variables are selected to solve optimization problem. The average of principal couplings and output strain levels are chosen as the objective function and the constraints respectively. An effective optimization framework is suggested, which utilizes interaction between FEM software ANSYS and MATLAB by using morphing technique. As a result of optimization, the biggest coupling error is reduced from about 35% to 2.5%, which is satisfactory for use of mechanically decoupled six-axis F/T sensors. Experimental verification is conducted and it is shown that there is maximum 5.1 % difference in strain outputs of numerical and experimental results, which verifies the validity of suggested FE model. The design formulation and framework proposed in this study are expected to promote researches on multi-axis F/T sensors and their commercialization in various industries.