Cellulose nanofibrils (CNF) can be produced in the form of thin, transparent andflexible films. However, the permeability of such materials to oxygen and water vaporis very sensitive to moisture, which limits their potential for a variety of packaging andencapsulation applications. Diffusion barrier coatings were thus developed to reducethe access of water molecules to enzymatically pre-treated and carboxymethylated CNFsubstrates. The coatings were based on UV curable organic-inorganic hybrids withepoxy, tetraethylorthosilicate (TEOS) and 3-glycidoxypropyltrimethylenesilane (GPTS)precursors and additional vapor formed SiNx layers. A total of 14 monolayer andmultilayer coatings with various thickness and hybrid composition were produced andanalyzed. The water vapor transmission rate (WVTR) of the bilayer epoxy/CNF film wastwo times lower compared to that of uncoated CNF film. This was partly due to the watervapor permeability of the epoxy, a factor of two times lower than CNF. The epoxy coatingimproved the transparency of CNF, however it did not properly wet to the CNF surfacesand the interfacial adhesion was low. In contrast hybrid epoxy-silica coatings led to highadhesion levels owing to the formation of covalent interactions through condensationreactions with the OH-terminated CNF surface. The barrier and optical performance ofhybrid coated CNF substrates was similar to that of CNF coated with pure epoxy. Inaddition, the hybrid coatings provided an excellent planarization effect, with roughnessclose to 1 nm, one to two orders of magnitude lower than that of the CNF substrates.The WVTR and oxygen transmission rate values of the hybrid coated CNF laminateswere in the range 5–10 g/m2/day (at 38◦C and 50% RH) and 3–6 cm3/m2/day/bar (at23◦C and 70% RH), respectively, which matches food and pharmaceutical packagingrequirements. The permeability to water vapor of the hybrid coatings wasmoreover foundto decrease with increasing the TEOS/GPTS ratio up to 30 wt% and then increase athigher ratio, and to be much lower for thinner coatings due to further UV-induced silanolcondensation and faster evaporation of byproducts. The addition of a single 150 nmthickSiNx layer on the hybrid coated CNF improved its water vapor barrier performance bymore than 680 times, with WVTR below the 0.02 g/m2/day detection limit.