This study focused on applying different high hydrostatic pressure + carbon dioxide (HHP + CO2) processing conditions on refrigerated (4 degrees C, 25 days) farmed coho salmon (Oncorhynchus kisutch) to inactivate endogenous enzymes (protease, lipase, collagenase), physicochemical properties (texture, color, lipid oxidation), and microbial shelf life. Salmon fillets were subjected to combined HHP (150 MPa/5 min) and CO2 (50%, 70%, 100%). Protease and lipase inactivation was achieved with combined HHP + CO2 treatments in which lipase activity remained low as opposed to protease activity during storage. Collagenase activity decreased approximately 90% during storage when applying HHP + CO2. Combined treatments limited the increase in spoilage indicators, such as total volatile amines and trimethylamine. The 150 MPa + 100% CO2 treatment was the most effective at maintaining hardness after 10 days of storage. Combined treatments limited HHP-induced color change and reduced the extent of changes caused by storage compared with the untreated sample. Microbial shelf life was extended by the CO2 content and not by the HHP treatments; this result was related to an increased lag phase and decreased growth rate. It can be concluded that combining HHP and CO2 could be an effective method of inactivating endogenous enzymes and extend salmon shelf life.