Significance Muscles, composed of exquisite hierarchical structures, exhibit high fatigue resistance and can resist crack propagation even after injury. The mechanism of the hierarchical structures on suppressing crack advance under reciprocating movement is poorly understood. Tough and self-healing hydrogels are good candidates as simplified model systems for studying the mechanical behaviors of load-bearing biotissues. Here, we report that polyampholyte hydrogels, having a hierarchical structure, demonstrate high fatigue resistance through a synergistic effect between different scales. Such an antifatigue mechanism based on hierarchical structure not only gives important hints to understand fatigue-resistant behavior of biotissues with complex hierarchical structures, but also provides design strategy for tough and fatigue-resistant hydrogels, by forming multiscale network structures using noncovalent bonds as building blocks.