The disintegration under composting conditions of films based on poly(lactic acid)-poly(hydroxybutyrate) (PLA-PHB) blends and intended for food packaging was studied. Two different plasticizers, poly(ethylene glycol) (PEG) and acetyl-tri-n-butyl citrate (ATBC), were used to limit the inherent brittleness of both biopolymers. Neat PLA, plasticized PLA and PLA-PHB films were processed by melt-blending and compression moulding and they were further treated under composting conditions in a laboratory-scale test at 58 ± 2 °C. Disintegration levels were evaluated by monitoring their weight loss at different times: 0, 7, 14, 21 and 28 days. Morphological changes in all formulations were followed by optical and scanning electron microscopy (SEM). The influence of plasticizers on the disintegration of PLA and PLA-PHB blends was studied by evaluating their thermal and nanomechanical properties by thermogravimetric analysis (TGA) and the nanoindentation technique, respectively. Meanwhile, structural changes were followed by Fourier transformed infrared spectroscopy (FTIR). The ability of PHB to act as nucleating agent in PLA-PHB blends slowed down the PLA disintegration, while plasticizers speeded it up. The relationship between the mesolactide to lactide forms of PLA was calculated with a Pyrolysis-Gas Chromatography-Mass Spectrometry device (Py-GC/MS), revealing that the mesolactide form increased during composting.