Despite the great potentialities of nanotechnology for food packaging applications, there are still a number of important issues to consider, mainly regarding the safety concerns and the industrial scale‐up. A feasible solution to overcome the problem of possible nanoparticles migration can be the use of a functional barrier between the nanomaterial and the food. In this work, multilayer packaging films, incorporating a layered silicate/polyamide nanocomposite (as oxygen barrier layer) and low‐density polyethylene (as moisture resistant and sealable layer) in direct contact with food, were produced by a lab‐scale blown co‐extrusion equipment using different processing conditions and film layouts, to determine the key parameters for performance improvement and to assess their potential applicability on an industrial scale. In particular, a copolyamide 6,66 was used as polymer matrix and two organomodified layered silicates (Cloisite 30B and Dellite 43B) were selected as nanofillers. The results demonstrated the potential technological interest of the proposed packaging solutions in terms of increased performances and ecofriendliness because all the multilayer hybrid films, particularly the ones filled with Cloisite 30B, display significant improvements in barrier and mechanical properties not only with respect to the corresponding unfilled systems, but also compared to similar PA/PE commercial films. The observed increments, up to 60% for oxygen barrier and 55% for stiffness, are more relevant in the case of the films with the thinner nanocomposite layer. Moreover, no detectable changes in film ductility, optical properties, and overall migration behavior were measured as consequence of nanofiller addition. POLYM. COMPOS., 39:3157–3167, 2018. © 2017 Society of Plastics Engineers [ABSTRACT FROM AUTHOR]