In this paper, an energy-efficient cyber-physical system using piezoelectric transducers (PZTs) and wireless sensor networks (WSN) is proposed, designed and experimentally validated for on-board aircraft structural health monitoring (SHM). A WSN is exploited to coordinate damage detection using PZTs distributed on the whole aircraft. An active sensing methodology is adopted for PZTs to evaluate the structural integrity in a pitch-catch manner. The system configuration and operation principle are discussed in the first place. Then, the detailed hardware design was introduced. The proposed system is not only characterized as low-power, high-compactness and wireless, but also capable of processing actuating-sensing signals at megahertz, generating actuating signals with great flexibility, handling multiple actuating-sensing channels with marginal crosstalk. The design was implemented on a 4-layer printed circuit board (8 × 6.5 cm) and evaluated on a large-scale composite fuselage. A 5 MHz sampling rate for actuating and 1.8 MHz for sensing (8 channels) were realized, and the accuracy was validated by comparing the results with those from an oscilloscope. The crosstalk issue caused by actuation on sensing channels is properly addressed using a 2-stage attenuation method. An ultra-low current (81.7 μA) was measured when no detection was required; the average current was 0.45 mA with a detection rate of twice per hour, which means the system can continuously work for up to 12.6 months for 2 AA batteries. Eventually, an example of damage detection is provided, showing the capability of such a system in SHM.