Pressure-assisted thermal sterilization (PATS) utilizes flexible packaging with low oxygen and water vapor transmission rates (OTRs, WVTRs). In this study, pouches made from metal oxide (MO)-coated (A–D) and ethylene vinyl alcohol (EVOH)-containing (E, F) multilayer films were filled with water and mashed potatoes (MP), preheated at 98 ± 0.5 °C for 10 min, and processed using a pilot-scale high-pressure processing machine (HPP) at 600 ± 5 MPa for 300 s. The initial vessel temperature and the fluid medium were 90 °C, and during processing, the temperature of the fluid medium increased to approximately 120 °C. After processing, the water-filled pouches were emptied, refilled with a novel oxygen indicator, and stored at 40 ± 0.2 °C for 80 days. The MP-filled pouches were stored at 49 ± 1 °C for 60 days. MO-coated film D contained fewer defects, had ultra-low OTRs and WVTRs, showed insignificant (p > 0.05) moisture absorption and changes in crystallinity after PATS processing, and exhibited minimal color change in both the oxygen indicator and the packaged MP during the 60 days of storage. The ultra-high barrier of film D could be attributed to the presence of multiple AlOx-coated PET layers that successfully prevented oxygen ingress, even after exposure to high temperature and pressure conditions during PATS processing. Among the EVOH-based structures, the Film F showed a 22.3 % lower OTR than Film E (p < 0.05), due to a 16.7 % greater EVOH-layer thickness, despite having a lower overall thickness than Film E. Overall, this study can assist packaging manufacturers in designing and developing high-barrier flexible packaging suitable for in-package, shelf-stable food products.