As a widely used nuclear structural material, zirconium (Zr) alloys are susceptible to brittle hydride-induced cracking. The intrinsic inability to arrest this cracking tendency in Zr poses a significant threat to the service safety of Zr cladding tubes. Here, we propose a microstructural design strategy, by introducing a hierarchical nanolayered duplex-phase structure in the Zr-2.5Nb alloy, to effectively inhibit the propagation of cracks. An unprecedented fracture toughness of KJIc ∼ 165 MPa·m1/2, corresponding to JIc ∼ 256 kJ/m2, is achieved due to the uniform and dense plastic deformation that develops ahead of the crack tip, which is uncharacteristic of Zr-based materials. Our analysis reveals that the effective crack tip blunting occurs because the high density of multiply oriented α/β interfaces in the hierarchical Zr-2.5Nb alloy stimulates ample <c+a> dislocations and facilitates deformation twin nucleation, both of which are challenging to activate in conventional Zr-based materials at room temperature. The exceptional fracture toughness enabled by the hierarchical nanolayered structure provides a new pathway to designing damage-tolerant hexagonal metals for safety-critical applications.