Psychotherapists’ mental health has been traditionally associated with the harmful consequences of clinical practice. In contrast to this dominant model, a growing body of research in positive psychology has sparked an interest in therapists’ positive well-being. The main objective of this study was to examine the relations between therapists’ epistemic orientation modes, emotion regulation strategies and psychological well-being (PWB). This was a cross-sectional study in which participants were 674 therapists (78.5% women), with a mean age of 42.02 years (SD = 13.06). Therapists completed an online questionnaire containing self-report measures of all study variables. Structural equation modelling using latent variables was performed to test the study hypotheses. Results revealed no significant direct effects of epistemic orientation on PWB. Up- and downregulation strategies had the most substantial direct effects on total PWB. Furthermore, emotion regulation mediated the association between therapists’ epistemic orientation modes and PWB, accounting for 57% of the variance in the outcome variable. Implications for training, practice and therapist self-care are discussed.