In this study, the orientation dependent hardness and creep properties of heavy ion irradiated Zr-2.5Nb pressure tube alloy are investigated by nanoindentation. The indentation tests are conducted along the axial direction (AD) and the transverse direction (TD) relative to the tube. TD samples demonstrate a dependence of the indentation size effect on irradiation damage, which is related to the decrease of the plastic zone size as irradiation damage increases. The hardness of AD and TD samples shows linear dependence on the square root of the irradiation damage density. The transition of the flow pattern from laminar to rotational flow happens in TD samples when the indentation is deeper than 1 μm; rotational flow is expected to be dominant after irradiation. AD samples exhibit laminar flow regardless of indentation depth or irradiation damage. The creep distance is increased for AD while it decreased for TD after irradiation. The creep process in the unirradiated materials and irradiated TD samples is found to be plasticity creep (dislocation glide plus climb). However, for AD samples, the mechanism is changed to power-law creep after 0.6 dpa irradiation. Both the hardness and creep results can be related to the anisotropic deformation mechanisms in the samples.