Growing concerns regarding climate change have heightened interest in utilizing carbon dioxide as a valuable carbon source for chemical production. The acetogen Thermoanaerobacter kivui is a thermophilic bacterium that converts CO2 and H2 streams into acetic acid. Nevertheless, the limited solubility of the gaseous substrates in the liquid medium has often led to low productivity by the biocatalyst employed. This study aims to enhance the cell-specific acetic acid productivity of T. kivui by combining pressure, the composition of the inlet gas mix, and in-flow gas rate. Firstly, the combined effect of pressure and gas composition was assessed through a Design of Experiments approach. Tests were performed in a pressurized bioreactor and indicated that acetic acid cell-specific productivity was achieved at 10 bar, providing a 3:1 H2:CO2 blend. Subsequently, supplying this blend at high pressure into the vessel of the reactor, an in-flow gas rate screening was performed to identify completely the parameters that allowed the maximum acetic acid productivity. The optimal flow rate was 60 mL.min−1, and the acetic acid cell-specific productivity reached 2.90 g.g−1.h−1. Additionally to the experiments in the bioreactor, tests in serum bottles were performed to investigate the influence of the osmotic condition due to different salts and acetic acid inhibition on T. kivui. Results indicated that salts and acetic acid concentration impaired bacteria growth and affected the production of further acetic acid. Nevertheless, a metabolic shift toward the production of formic acid was observed specifically by adding the HCO3– ion.