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Abstract Recent developments of micro‐sensors and flexible electronics allow for the manufacturing of health monitoring devices, including electrocardiogram (ECG) detection systems for inpatient monitoring and ambulatory health diagnosis, by mounting the device on the chest. Although some commercial devices in reported articles show examples of a portable recording of ECG, they lose valuable data due to significant motion artifacts. Here, a new class of strain‐isolating materials, hybrid interfacial physics, and soft material packaging for a strain‐isolated, wearable soft bioelectronic system (SIS) is reported. The fundamental mechanism of sensor‐embedded strain isolation is defined through a combination of analytical and computational studies and validated by dynamic experiments. Comprehensive research of hard‐soft material integration and isolation mechanics provides critical design features to minimize motion artifacts that can occur during both mild and excessive daily activities. A wireless, fully integrated SIS that incorporates a breathable, perforated membrane can measure real‐time, continuous physiological data, including high‐quality ECG, heart rate, respiratory rate, and activities. In vivo demonstration with multiple subjects and simultaneous comparison with commercial devices captures the SIS's outstanding performance, offering real‐world, continuous monitoring of the critical physiological signals with no data loss over eight consecutive hours in daily life, even with exaggerated body movements.