Undesirable vibration of aircraft panel structures has a significant impact on the safety of their occupants and the operational reliability of various systems. The traditional time-domain controller based on the parallel multi-frequency filtered-x least mean square (FxLMS) control algorithm is simple and effective. However, the mutual influence of convergence steps and the induced harmonic components will limit its performance. An improved parallel multi-input multi-output multi-frequency FxLMS (MIMOMF-FxLMS) algorithm is proposed, considering the multi-input multi-output (MIMO) control requirement of the aircraft panel structure active vibration control (AVC) system and its inevitable channel coupling phenomenon. The feedback error signal and the control channel model are processed by frequency division in the MIMOMF-FxLMS algorithm, so that the FxLMS algorithm of each control channel runs independently, effectively avoiding mutual interference between convergence steps and the generation of induced harmonic components. Simulation and experimental research on multi-frequency AVC of the panel structure model is performed using a new type of piezoelectric stack actuator. The test results show that the proposed controller reduces the vibration level of each observation point by more than 98%, and the vibration responses of the first two-order frequency component are significantly suppressed, which also has strong adaptability and anti-noise ability.