The preservation effect of modified atmosphere packaging (MAP) on seafood has been applied widely, but packaging with high concentrations of CO₂ will have adverse effects on seafood. This study aimed to elucidate the potential mechanism of the adverse effects caused by MAP with high CO₂ concentration at 4 °C. The changes in the quality of salmon fillets under high concentrations of CO₂ packaging were demonstrated in this article through indicators such as total volatile basic nitrogen content, microbial counts, thiobarbituric acid reactive substances (TBARS) value, and drip loss. The underlying mechanisms were further explained from the perspectives of protein degradation and endogenous enzymes. The study indicated that the microbial counts in the 90% CO₂/10% O₂ group were higher than both the 75% CO₂/10% O₂/15% N₂ and 60% CO₂/10% O₂/30% N₂ groups on the 12^th day, and there was also an increase in TBARS value and drip loss. On the 2^nd day, the caspase-3 relative activity in the 90% CO₂/10% O₂ group (119.96%) was found to be higher than the 75% CO₂/10% O₂/15% N₂ group (111.99%). On the 12^th day, the relative activities of caspase-3 in the 90% CO₂/10% O₂ group and the 75% CO₂/10% O₂/15% N₂ group were 34.13% and 25.77%, respectively, the latter exhibited the lowest cathepsin activity and the minimum myofibril fragmentation index. The results of free amino acids analysis indicated that the 90% CO₂/10% O₂ group was also accompanied by an accumulation of more bitter amino acids during storage. The MAP with 75% CO₂ had better effect on inhibiting caspases and cathepsins, which could be the main reason to a better muscle quality of salmon fillets at 4 °C.