In order to investigate the effect of crystallographic orientation on the nano-indentation behaviors of single crystal super alloys, the nano-indentation experiments with a Berkovich indenter in an atomic force microscope were carried out on [001], [011] and [111] oriented Nickel based single crystal super alloys. Experimental results showed that the indentation load-depth curve, hardness and elastic modulus were remarkably influenced by crystallographic orientation. It is found that the shape and volume fraction of γ^" strengthening phase is dependent on crystallographic orientation, which will influence the mechanical properties. The nano-indentation experiments performed on three typical crystallographic orientations were simulated by using crystal plasticity theory to investigate the indentation responses and the resolved shear stress induced by indentation, and the simulation results showed a good agreement with the experiment results.