With the repeated cycles of aircraft take-off-cruise-landing, the composite honeycomb sandwich structures undertakes pressure differential loads. To research the influence of the repeated ground-air-ground pressure differential loads on the delamination propagation behavior, a test fixture was designed to apply compression loads while applying pressure differential loads simultaneously. Cyclic load tests were performed with composite honeycomb sandwich panel specimen, within which a delamination of diameter 30 millimeters was embedded. One set specimen were tested by compression fatigue loads, as contrast, another set specimen were tested under compression fatigue loads combined with repeated pressure differential loads. The teardown inspection of failed specimen shows that the delamination grows in the bondline in the direction vertical to the loading direction. Under the compression fatigue loads level of about 80% ultimate load, the delamination grows slowly in the initial stage and then accelerates when the delamination size becomes big enough. Compared with the specimen only tested by repeated compression load, the delamination growth rate is much higher in the specimen tested by the combination of repeated compression loads and pressure differential loads. Finite element analysis was then performed, and the results show that the out-of-plane peeling stress between the composite skin panel and the honeycomb caused by the pressure differential load is the main driving force for the accelerated delamination propagation.