Fixture layout optimization is a procedure to optimize position of locators and clamps in order to minimize specified objectives. Deformation of workpiece is a serious problem of concern while designing a fixture. Proper positioning of fixture elements is indispensable to achieve desired machining accuracy, better surface finish and high productivity. In this work, a novel methodology is proposed that incorporates full factorial design of experiments and statistical analysis. Furthermore, the stability of the workpiece is ensured prior to the prediction of objective function. The result of the proposed technique is compared with the results of the genetic algorithm–based optimization technique. A case study has been considered to evaluate the proposed methodology. The objective function determines maximum elastic deformation of the workpiece during the entire machining process. Finite element method is used to formulate the objective functions. The constraints are natural frequency of the workpiece–fixture system and reaction forces. Besides, artificial neural network–based model is developed to predict the elastic deformation of the workpiece–fixture system within the range of design parameters.