Abstract: To characterize the dynamic response of aircraft honeycomb sandwich structures subjected to spatially nonuniform water ingress, hygrothermal conditions, and high–low-temperature cycling, a hygro-thermo-mechanical model of water-ingressed honeycomb sandwich panels was developed. A Python-based secondary development of ABAQUS was implemented, and Monte Carlo sampling without replacement was employed to generate random water-ingress models with water-volume fractions ranging from 10% to 40%. Modal analyses were performed under free–free boundary conditions, and the finite-element model was evaluated using modal tests on intact and specimens with a water-volume fraction of 20% under different temperatures and cycle numbers. An equivalent stiffness retention coefficient was further identified from the first natural frequency measured in the 20% water-ingress cycling test. The cycle number was introduced into the finite-element model by reducing the elastic and shear moduli, and the cyclic responses at different initial water-volume fractions were subsequently predicted. The results showed that, for the 100 random realizations generated at each water-volume fraction, the cumulative means of the first three natural frequencies became stable when the sample size reached 20. The relative differences between the random and homogenized models ranged from 0.28% to 0.84%. At 300 K and a water-volume fraction of 20%, the average relative errors of the first three natural frequencies were 6.59% and 7.10% for the random and homogenized models, respectively. The main advantage of the random model was its capability to characterize the frequency variability induced by spatially nonuniform water ingress. When the water-volume fraction increased from 10% to 40%, the first three natural frequencies of the random model decreased by 9.99%, 6.53%, and 5.65%, respectively. When the temperature increased from 300 K to 350 K, the first natural frequency of the specimen with 20% water ingress decreased by 6.46%. The frequency reduction became more pronounced after 100 high–low-temperature cycles, and after 200 cycles, the first three natural frequencies of the 20% water-ingress specimen decreased by 16.68%, 18.82%, and 21.18%, respectively. Under the assumption that different initial water-volume fractions share the same equivalent stiffness-reduction law, the numerical predictions indicated that a higher initial water-volume fraction intensified the cyclic frequency reduction. The findings provide a theoretical basis for dynamic performance evaluation and damage management decision-making of aeronautical honeycomb sandwich structures.