Background: GPs are particularly vulnerable to job burnout. Tailored prevention and intervention strategies are needed. Aim: To investigate organisational, interpersonal, and individual factors contributing to exhaustion and disengagement at work among GPs. Design & setting: We conducted a cross-sectional study in a sample of Belgian GPs. Method: A total of 358 doctors (73% females, 301 with complete data) completed an online anonymous questionnaire assessing job burnout, psychosocial characteristics of the work environment, perceived social support in the private domain, emotional competence, and self-compassion. Results: GPs reported moderate levels of exhaustion and disengagement. Regression models showed that included factors jointly explained 69% of the variance in exhaustion and 63% in disengagement. Exhaustion was significantly predicted by female sex (β effect size = −0.1), high perceived emotional demands (β = 0.19), as well as low self-compassion (β = −0.14) and low emotional competence (β = 0.09). Disengagement was significantly predicted by low seniority (β = −0.12) and limited opportunities for development (β = −0.16). Both exhaustion and disengagement were predicted by low perceived quality of work (β = −0.19 and −0.14, respectively), meaning of work (β = −0.17 and −0.31, respectively), and role clarity (β = 0.09 and 0.12, respectively), as well as high perceived work–life conflict (β = 0.46 and 0.21, respectively). Moreover, GPs working in a multidisciplinary group reported lower levels of exhaustion and disengagement than those working in a monodisciplinary group or a solo practice, and this difference was associated with factors such as work–life conflict. Conclusion: Organisational, interpersonal, and intrapersonal factors interact to predict a substantial part of burnout in general practice. The most significant risk factors were perceived work–life conflict and poor meaning of work. Policymakers should work to support more sustainable practices based on the specific needs and constraints ...