Hybrid nanocomposites based on high-density polyethylene (HDPE)/poly (ethylene- co -vinyl alcohol) (EVOH)/clay were prepared and fully characterized. Morphological (WAXS and TEM), calorimetric (DSC), and dynamic mechanical thermal (DMTA) analyses were applied to investigate potential of nanocomposites as barrier against oxygen. Co-existence of ingredients of different nature, i.e. HDPE (general-purpose non-polar component), EVOH (engineering polar component with excellent barrier properties), nanoclay (planar one-dimensional mineral barrier nanofiller), and maleated HDPE (PE- g -MA) as coupling agent, brings about serious intricacies in view of interaction between existing phases. Conceptual/experimental analysis was performed to explore the interdependence between microstructure and oxygen barrierity of HDPE/EVOH/clay nanocomposites through the lens of interaction state in the system. Morphological measurements confirmed formation of an intercalated nanostructure, while investigations on complex viscosity, storage modulus, permeability, thermo-mechanical properties, and nanoclay interlayer galleries were all indicative of dependence of nanocomposites’ properties on molecular interactions. The performance of nanocomposite sheets as oxygen barriers was mechanistically explained.