Fully bio-based and biodegradable materials, such as polylactic acid (PLA) and microfibrillated cellulose (MFC), are considered in order to produce a completely renewable packaging solution for oxygen barrier applications, even at medium-high relative humidity (R.H.). Thin layers of MFC were coated on different PLA substrates by activating film surface with an atmospheric plasma treatment, leading to the fabrication of robust and transparent multilayer composite films, which were then characterized by different experimental techniques. UV transmission measurements confirmed the transparency of multilayer films (60% of UV transmission rate), while SEM micrographs showed the presence of a continuous, dense and defect free layer of MFC on PLA surface. Concerning the mechanical behavior of the samples, tensile tests revealed that the multilayer films significantly improved the stress at break value of neat PLA. Moreover, the oxygen barrier properties of the multilayer films were improved more than one order of magnitude compared to neat PLA film at 35 °C and 0% R.H. and the permeability values were maintained up to 60% R.H. The obtained materials therefore showed interesting properties for their possible use in barrier packaging applications as fully biodegradable solution, coupling two primarily incompatible matrices in a multilayer film with no need of any solvent or chemical.