The barrier property of polypropylene (PP)/polyamide (PA) blend film produced by the extrusion casting film process was studied by investigating the effects of rheological properties of each components, compatibilizer content, screw rpm, and the absorbed moisture, and by performing morphological analysis and permeability modeling. The oxygen barrier property of blend film with ellipsoidal structure of PA dispersed phase was significantly improved by a factor of 5.4 with the addition of only 20 wt% PA, when compatibilizer was added by the content of 7 phr and the PP matrix resin and process condition was selected to induce lower viscosity ratio less than unity. Using Fricke’s model with the value of 19.6 of aspect ratio of the ellipsoid, the permeabilities of blend films as a function of PA content could be predicted and exhibited a good agreement with the experimental results. The absorbed moisture had a significant influence on the barrier property of the PP/PA blend system, suggesting that the hygroscopic PA resin should be incorporated with the high water barrier PP resin by the amount below about 20 wt% to minimize the deterioration of the barrier property in the humid atmosphere.