As a representative of hcp/bcc metallic multilayers, the correlation between microstructures and mechanical properties of nanostructured Zr/Mo multilayers with were studied. Zr/Mo multilayers with different layer thicknesses were prepared by magnetron sputtering method. XRD and TEM analyses revealed that Zr/Mo multilayers have Zr (0002) and Mo (110) out-of-plane crystalline texture. The nanoindentation hardness of Zr/Mo multilayers is in the range of ∼9.9–10.8 GPa at h ≤ 10 nm, while decreases with reducing layer thickness at larger h, which is on the contrary of the common rule - smaller is stronger. The aforementioned strengthening mechanism applicable in multilayers, i.e., dislocation bowing-out in nanolayers is not suitable to explain this size dependent softening behavior, while the IBS model fits well with the measured hardness at h = 10 nm. This anomalous softening behavior at large layer thickness scales may be caused by its special structures and deformation mechanisms. Dislocations interact with the grain boundaries, instead of the interfaces, and grains rotation/grain boundaries sliding are the dominant deformation mechanism at large layer thickness scales. The size-dependent strain rate sensitivity and activation volume were also explored, to revealing the rate dependent deformation mechanisms.