Background: Chronic pain is associated with increased disability and vulnerability to emotional disorders. Personality and psychological flexibility (PF) describe interindividual differences that shape the adjustment to chronic pain. Specifically, PF was found to be associated with pain, fatigue, anxiety, and depression intensity. Although previous studies established strong correlations between personality and pain outcomes, evidence on the nature of this relationship is scarce. Therefore, the objective of this study is to explore the mediating effect of PF on the relationship between personality and distress. Methods: This transversal study included 108 participants (age M = 56.7, SD = 11.3) diagnosed with musculoskeletal chronic pain. Self-reported measures were administered by the medical care team. Multiple mediation models were performed for estimating the indirect effects on each outcome variable. Results: After controlling for age and gender covariates, we found that PF completely mediated the relationship between personality traits and all pain outcomes and partially mediated the impact of extraversion on anxiety. In addition, emotional stability also had an indirect effect on anxiety through PF. Conclusions: Personality traits and PF are significant predictors of pain outcomes. PF represents a core process mediating the impact of personality traits on the perceived intensity of pain, fatigue, anxiety, and depression in patients with rheumatic disease. These results could facilitate the application of individualized psychological interventions in clinical contexts targeting the reduction of emotional avoidance and in chronic pain patients.