A combined treatment based on high-pressure carbon dioxide and high-power ultrasound (HPCD + HPU) technologies was investigated for the pasteurization of fresh-cut coconut. Inactivation kinetics of both the natural microbiota and Salmonella enterica typhimurium spiked on the product were determined at 12 MPa and 10 W, delivered every 2 min of treatment, as a function of temperature (from 24 to 50 °C) and treatment time (from 5 up to 30 min). Additionally, to study the effect of HPCD + HPU on the quality of the product, physicochemical attributes (total acidity, pH, color, texture, dry matter, fat content, enzymatic activity, antioxidant capacity, phenols, flavonoids, and phenolic acids) were measured after the combined treatment and during a refrigerated shelf life of 4 weeks. The results revealed that HPCD + HPU increased microbial inactivation rates compared with HPCD alone: 8 log reductions of S. typhimurium were achieved with HPCD + HPU at 12 MPa, 40 °C, 20 min, while just a 4 log reduction was achieved with HPCD alone. Similar results were obtained for the natural microbiota; milder conditions of temperature and pressure were sufficient to assure inactivation to undetectable levels even of mesophilic microorganisms, the most resistant ones. Total acidity and pH did not change after the combined treatment and during the entire storage of 4 weeks, while slight differences were observed for the other physicochemical parameters. Overall, the results showed the feasibility and the potential of HPCD + HPU as an innovative non-thermal technology for the pasteurization of fresh-cut fruits.