The effects of high pressure (HP) and ficin treatments, and their combinations on the quality characteristics of post-rigor tan mutton were investigated. HP at 150 MPa/15 min significantly increased the hardness and centrifugal loss (CeL) of meat and deteriorated the meat color, and ficin at 0.10 g/L reduced meat hardness by 8% and protected meat color but increased CeL significantly (P < 0.05). Initial ficin (0.10 g/L) injection and incubation at 55 °C for 60 min, followed by HP at 50 MPa/15 min and 150 MPa/15 min reduced the hardness of the treated meat by 48% and 41% respectively, and cooking loss (CL) and CeL were also significantly decreased (P < 0.05), yet ficin combined with 150 MPa markedly increased the levels of thiobarbituric acid reactive substances (TBARS), lightness (L*) and yellowness (b*) of the processed meat. Water retentiveness and tenderness enhanced by combined treatments were found to be mainly attributed to increased degradation of myofibrillar and sarcoplasmic proteins through ANOVA-Partial least squares regression (APLSR), and sensory evaluation verified the high acceptability of the meat treated by both HP and ficin in terms of tenderness, flavour and texture after cooking. • A combination of ficin with HP produced synergistic effect on meat quality improvement. • Optimal combination conditions of ficin and high pressure were confirmed. • Key proteins associated with a combination of ficin with HP on meat tenderization were identified. • Ficin-assisted high-pressure (HP) tendering of meat was independent of the secondary structure of myofibrillar protein. [ABSTRACT FROM AUTHOR]