CO2-based poly(3-hydroxybutyrate) (PHB) can be produced by the versatile bacterium Cupriavidus necator in a chemolithoautotrophic fermentation, using a gas mixture consisting of CO2, H2, and O2. Despite offering a propitious route for carbon–neutral bioplastic manufacturing, its adoption is currently hampered by the wide explosive range of the required gas mixture, as well as the limited gas-to-liquid mass transfer rates. To address these challenges, pressure fermentation was applied as a robust and effective strategy, while ensuring safe operation by adhering to the limiting O2 concentration, utilizing state-of-the-art bioreactors. Consequently, exponential growth could be prolonged, boosting CO2-based PHB production from 10.8 g/L at 1.5 bar up to 29.6 g/L at 3 bar. The production gain closely aligns with the theoretical calculations, except for when the pressure was increased up to 4 bar. Overall, the demonstrated increase in PHB production underscores the potential of pressure fermentation to enhance chemolithoautotrophic fermentation.