High-pressure processing (HPP) is a novel non-thermal processing technology, ensuring the safety of food products, as well as preserving their nutritional and functional characteristics, and avoiding the harmful effects of traditional thermal technologies. This study examined the inactivation of microorganisms and the HPP kinetic model in fermented pomegranate juice (FPJ) at different pressures (400 MPa, 500 MPa, and 600 MPa), and different treatment times (3 min, 5 min, 7 min, and 10 min). Moreover, HPP and thermal processing (TP) (65°C/20 min) treatment responsible for a similar microbial inactivation activity, were compared by examining their impact on bioactive compounds, volatile compounds, and various quality attributes to provide a theoretical basis for FPJ processing. The inactivation curves of the microorganisms as a result of HPP were fitted using the Weibull model. Furthermore, HPP at or over 600 MPa/3 min inactivated the microorganisms and sufficiently retained the microbial populations investigated in this study below the detection limit. Following HPP and TP treatment, the total color difference (ÎE) values, total soluble solids (TSS), pH and titratable acidity (TA) had not significantly (p>0.05) changed. For total flavonoids, total phenols, anthocyanins, and antioxidant activity, the maximal retention of 91.18%, 97.52%, 95.69%, and 95.89% was achieved at 600 MPa/3 min, which was 4.62%, 24.61%, 26.83%, and 7.08% higher than in the TP-treated sample. The main volatile compounds in FPJ were esters and alcohols, and the FPJ treated at 600 MPa/3 min exhibited the highest alcohol content, while the esters were 2.27% higher than in the control. Considering the pasteurization effect and quality maintenance abilities of HPP and TP treatment, 600 MPa/3 min could be considered as an optimal condition in facilitating FPJ processing.