Single set-up fixtures in milling and drilling processes are usually desired because of its high efficiency. One of the main difficulties in designing such fixtures is to estimate the deformation corresponding to the processes under consideration. In this aspect, theoretical calculation of the workpiece deformation has hardly been achieved due to the complication caused by interactions between the cutting forces and clamping forces on the workpiece. Traditionally the workpiece deformation under a fixture is estimated approximately based on the designer’s experience. In this paper, a system for simulation of workpiece deformation in end milling and drilling processes is developed. In the system, from a given plan of fixture setup and machining conditions, the cutting forces and clamping forces acting on the workpiece are firstly predicted using theoretical and empirical models, then the corresponding deformations throughout the workpiece are calculated from the forces and workpiece material properties using the finite element method. As a case study, the system is used to investigate workpiece deformation in end milling a slot and drilling a hole on a workpiece with different configurations of single set-up fixture. It is shown that by using the simulation system the effect of different configurations of single set-up fixture on the deflections of the workpiece can be accurately estimated. In this way the feasibility of a single set-up fixture design can be studied and the design can be optimized on a scientific basis.