The potential of fatigue crack growth experiments to sensitively analyze the anisotropic mechanical behavior of injection-molded, multiphase polymer blends is presented. The properties of immiscible blends based on poly(2,6-dimethyl-1,4-phenylene ether) (PPE) and poly(styrene-co-acrylonitrile) is investigated, both in perpendicular and in parallel to the injection-direction. As a result of the limited interfacial adhesion and the orientation of the blend phases, the direction in parallel to flow revealed to be the weaker link. In order to enhance the toughness behavior, the PPE/SAN blends were systematically modified by the addition of different polystyrene-b-polybutadiene-b-poly(methyl methacrylate) triblock terpolymers (SBM), potentially acting as a compatibilizing and toughening agent. Such a compatibilization step of PPE/SAN blend leads to the formation of nanostructured morphologies. Depending on the composition of the triblock terpolymer, the resistance to crack growth was either further degraded or, in the case of high interfacial presence and compatibilization efficiency, significantly improved. The results were correlated to the fracture mechanisms of the blends as analyzed by scanning electron microscopy of the fracture surfaces. In contrast to poorly-compatibilized blends, a significant plastic deformation, an enhanced phase adhesion and a strongly reduced anisotropy could be detected in case of well-compatibilized blends. In summary, the presented study of the fatigue crack growth behavior revealed a detailed insight into the mechanical property profile of the selected multiphase blends and, moreover, demonstrated the potential of this method to sensitively analyze the anisotropy of such materials.