Anisotropic　hydrogels　are　promising　candidates　as　load-bearing　materials　for　tissue　engineering,　while　huge　challenges　remain　in　exploring　effective　and　scalable　methods　for　the　preparation　of　anisotropic　hydrogels　with　simultaneous　high　tensile　strength,　large　toughness,　good　fracture　strain,　excellent　fatigue　and　swelling　resistances.　Inspired　by　the　brick-and-mortar　layered　structure　of　nacre　and　the　hierarchical　fibril　strucure　of　soft　tissues　(e.g.,　tendon　and　ligament),　a　facile　organogel-assissted　calendering　strategy　is　reported　to　design　anisotropic　hydrogels　with　a　highly　oriented　and　dense　fiber　lamellar　strucure.　The　synergy　of　shearing　and　annealing　promotes　macromolecular　chain　alignment　and　crystallinity　along　the　calendering　direction　while　forming　a　nacre-like　lamellar　morphology　in　the　thickness　direction.　The　tensile　strength,　elastic　modulus,　toughness　and　fracture　energy　of　the　anisotropic　hydrogels　can　reach　as　high　as　41.0　±　6.4 MPa,　67.0　±　5.1 MPa,　46.2　±　3.3 MJ　m−3,　and　62.20　±　8.55 kJ　m−2,　respectively.　More　importantly,　the　hydrogels　show　excellent　crack　growth　and　swelling　resistances　with　the　fatigue　threshold　increased　to　2170　J　m−2.　This　study　provides　a　promising　approach　for　fabrication　of　large-sized　biomimetic　anisotropic　hydrogels　with　outstanding　mechanical　properties　for　biomedical　and　engineering　applications.　©　2025　The　Author(s).　Advanced　Science　published　by　Wiley-VCH　GmbH.