Recent research has found that psychological flexibility, the key construct of the Acceptance and Commitment Therapy (ACT) model of mental health and behavioral effectiveness, is related to, and longitudinally predicts, a wide range of work-related outcomes. Less research, however, has been dedicated to explore the role of psychological flexibility as a protecting factor for the development of burnout syndrome. The current study examined whether: (a) general psychological flexibility and work-related psychological flexibility accounted for additional variance in burnout symptoms relative to work factors and other work-related constructs such as work engagement, work satisfaction, and psychological empowerment; and (b) work-related psychological flexibility moderated the relationship between exhaustion and cynicism. A cross-sectional study was conducted with 209 Spanish workers from different companies who completed questionnaires assessing the constructs of interest. Hierarchical regression analyses showed that psychological flexibility and work-related psychological flexibility accounted for additional variance in burnout symptoms. The moderator analysis showed that the relationship between exhaustion and cynicism was higher among participants with low levels of work-related psychological flexibility as compared to participants with high levels. These results suggest that interventions aiming to increase psychological flexibility might prevent the development of burnout syndrome.