Three‐dimensional (3D) flexible electronics represent an emerging area of intensive attention in recent years, owing to their broad‐ranging applications in wearable electronics, flexible robots, tissue/cell scaffolds, among others. The widely adopted 3D conductive mesostructures in the functional device systems would inevitably undergo repetitive out‐of‐plane compressions during practical operations, and thus, anti‐fatigue design strategies are of great significance to improve the reliability of 3D flexible electronics. Previous studies mainly focused on the fatigue failure behavior of planar ribbon‐shaped geometries, while anti‐fatigue design strategies and predictive failure criteria addressing 3D ribbon‐shaped mesostructures are still lacking. This work demonstrates an anti‐fatigue strategy to significantly prolong the fatigue life of 3D ribbon‐shaped flexible electronics by switching the metal‐dominated failure to desired polymer‐dominated failure. Combined in situ measurements and computational studies allow the establishment of a failure criterion capable of accurately predicting fatigue lives under out‐of‐plane compressions, thereby providing useful guidelines for the design of anti‐fatigue mesostructures with diverse 3D geometries. Two mechanically reliable 3D devices, including a resistance‐type vibration sensor and a janus sensor capable of decoupled temperature measurements, serve as two demonstrative examples to highlight potential applications in long‐term health monitoring and human‐like robotic perception, respectively.