Muscles and some tough hydrogels can maintain perfect mechanical properties after millions of loading cycles owing to the anisotropic microstructures inside them. However, applications of intrinsic anisotropic microstructures in biological tissues and tough hydrogels are limited by the poor mechanical performance in the perpendicular direction relative to the alignment direction. Here, a universal strategy is proposed for developing hydrogels with unprecedented isotropic crack propagation resistance only depending on the interpenetrating entanglements of polymer chains (polyacrylamide (PAAM) or poly‐(1‐acrylanmido‐2‐methylpropanesulfonic acid) (PAMPS)) in deformable polymeric microspheres (PAMPS or PAAM). The deformable interpenetrating network in microspheres can transform the hydrogel from isotropic to anisotropic instantaneously in any load direction, and effectively alleviate the stress concentration at the crack tip, dissipate energy, and eliminate notch sensitivity. The best isotropic hydrogel displays an ultimate strain of 5300%, toughness of 18.9 MJ m–3, fracture energy of 157 kJ m–2, and fatigue threshold of 4.2 kJ m–2. Furthermore, the mechanical strength of hydrogels can be simply tuned by solvent replacement. The strategy presented here can be expanded to prepare other isotropic hydrogels with super tear‐resistant and anti‐fatigue properties, based on a wide variety of deformable microspheres and matrix polymers. A universal strategy for the preparation of hydrogels with isotropic and unprecedented crack propagation resistance is presented. The hydrogels integrate the seemingly contradictory mechanical properties such as ultra‐stretchability, fatigue resistance, tear resistance, and high toughness by the interpenetrating entanglements of polymer chains in the deformable polymeric microspheres. The prepared hydrogel displays a strain of 5300%, toughness of 18.9 MJ m–3, fracture energy of 157 kJ m–2, and fatigue threshold of 4.2 kJ m–2.