Natural materials in human body (e.g. heart valves, cartilages and muscles) can undergo millions of cycles without losing their functionality. However, synthetic hydrogels including recent developed tough hydrogels are susceptible to fatigue-fracture even under a few thousands of cycles. To date, there are no unraveled mechanisms proposed yet to design anti fatigue-fracture hydrogels, which limits synthetic hydrogels’ applications that require long-term robust performance. Here, we report a biomimetic strategy to design anti fatigue-fracture hydrogels via controlled crystal domains. The strategy is to form percolated crystal networks in semi-crystalline hydrogels, retarding crack initiation under cyclic loading owing to high-strength crystal. To validate the proposed strategy, we use the poly(vinyl alcohol) (PVA) hydrogel as an exemplar material system and adopt a new experimental method to measure the fatigue threshold of the semi-crystalline networks with controlled crystal morphology. We show that the critical fracture energy for fatigue-fracture (i.e. fatigue threshold) can increase up to 1000 J/m2 as the crystallinity in semi-crystalline network reaches the percolation threshold, higher than that of existing reported hydrogels in the order of 1-100 J/m2. Following the design strategy, we further demonstrate two approaches to improve long-term mechanical performance: enhancing fatigue threshold via inducing local crystal domains around crack tip and achieving long-term high strength with crystal reinforcement.