The characterization and prediction of multiaxial fatigue of composite structures have become a very important topic since aircraft composite structures and their repaired bonded structures are unavoidably subjected to cyclic multiaxial loads with variable amplitudes and distinct phase angles. Two inherent challenges associated with the fatigue damage assessment of an aircraft structural component are the accurate determination of fatigue damage accumulation under multiaxial loading with limited fatigue test data and the scalability of a validated analysis tool for life assessment of a full-scale structure. A thoughtful and rational design of multiaxial fatigue tests of composite materials is essential to extract useful information for the characterization of failure mechanisms under a well-defined stress state as well as the verification and validation of an analysis tool under pre-defined mode mixity, applied load ratios, and phase angles between load components. Given the limited studies in understanding the multiaxial fatigue behavior of carbon fiber reinforced polymer (CFRP) composites and the strong need to support design certification and sustainment of aircraft composite wing structures, a combined experimental and numerical study is performed using enhanced design of cruciform specimens to validate and demonstrate our high-fidelity progressive damage prediction toolkit as the intermediate stage towards the full demonstration using the full-scale composite wing section. The existing fatigue analysis module is improved by including the local stress ratio and mode mixity dependent fatigue damage initiation description and a cycle jumping approach to capture the change in fatigue damage accumulation rate due to stress redistribution. The measured load-deflection and Digital Image Correlation (DIC) data from static tests are compared with the model prediction. In addition, measured stiffness degradation against cycles is compared with the predicted fatigue results. Both static and fatigue results show that the surface fiber cracks initiate and propagate along the orientation of the initial elliptical notch and the resulting stress concentration from the propagation of the fiber crack promotes matrix cracking and inter-ply delamination.