The objective of this study was to systematically examine the effect of high‐pressure processing and package headspace on package integrity and properties. Working pressures were 400 and 600 MPa, and starting vessel temperatures were 30°C, 60°C, and 90°C. Coextruded and laminated multilayers packaging films were studied: film A: (PA/EVOH/PP) and film B: (PET‐AlOx‐OC/PA6/PP), respectively. The films were made into pouches (0.05 m × 0.10 m) and filled with 30‐mL water as a model food. Various headspace volumes (0, 0.05, 0.10, 0.15, 0.20, 0.25, and 0.30‐cc air/mL H2O) were introduced into the packaging before processing. Imaging was used to quantify defects such as the formation of white spots on the package surface and delamination of film layers. The results showed that the headspace level and processing initial temperature had a greater effect than the operating pressure on visual defects. The package with 0% headspace did not show any physical damage to the tested films. Furthermore, thermal and mechanical analyses showed that the coextruded film A had better resistance to testing conditions than the laminated structure of film B. The X‐ray diffraction results showed that film B had more defects than film A that altered the crystalline structure. Visual observation revealed white spots and delamination in the inside layer (PP) in both films. The same processing conditions affected the oxygen and water vapour transmission rates of film B more than film A. This work provides a basic guideline to select the right headspace for a given type of packaged food whenever heat and pressure are used simultaneously.