1) Background: There are few studies of burnout syndrome (BS) in occupational therapists (OTs), and protective factors of BS has received little attention in the scientific literature. This research aimed to estimate the prevalence of BS, characterize the associated psychosocial factors, and analyze their relationship with health in a sample of Spanish OTs. (2) Methods A total of 127 therapists completed the Maslach Burnout Inventory (MBI) and other standardized questionnaires measuring: personality traits (reduced five-factor personality inventory, NEO-FFI), coping styles (Coping Strategies Questionnaire, CAE), work-family conflict (Survey Work-Home Interaction Nijmegen, SWING), professional factors (role ambiguity/clarity and modified role conflict questionnaires), and the perception of health (Goldberg’s General Health Questionnaire). Several correlational and multiple regression analyses were performed to study the psychosocial predictors of burnout and its relationship with health perception. (3) Results showed that 15.8% of the professionals presented BS, with emotional exhaustion (EE; 38.7%) being the most compromised dimension. Neuroticism, role conflict, negative work-family interaction, and open emotional expression (OE) significantly predicted a higher EE. The main predictors of cynicism (CY) were being male, role conflict, and OE. Finally, role conflict and role ambiguity and social support-seeking were significant predictors of reduced professional efficiency (PE). (4) Conclusion: A high percentage of OTs with BS advocates becoming aware of the importance of this syndrome in the health community, it would be critical to consider the protective factors (i.e., emotional management, social support) that help promote OTs’ well-being and health.