Background The optimal performance of doctors is critical to delivering high-quality, safe healthcare. However, 6–12% of doctors may experience challenges that impact their work performance. In many countries, including the UK, there is variation in the practice and quality of professional support services between different types of organisations. The aims of our study were (1) to identify why, how, in what contexts and for whom professional support works, (2) to develop a guide for healthcare organisations to use to optimise professional support. Methods We carried out a realist evaluation consistent with Realist And Meta-narrative Evidence Syntheses: Evolving Standards (RAMESES) II standards. 45 interviews were conducted with professional support staff and doctors who had undertaken professional support across seven sites in England. Interviews were analysed using a realist logic. To develop the guide, six workshops were held with the same groups plus a patient and public involvement group. Results We identified six principles of effective professional support, based on 47 context-mechanism-outcome configurations. (1) Work-place culture influences support-seeking behaviour. (2) Trust and psychological safety are central to enable candid conversations and engagement. (3) Doctors can then develop self-awareness and situational awareness, reframe challenges, accept responsibility where appropriate and recognise structural factors underpinning their difficulties. (4) Doctors are more likely to feel motivated to engage through positive framing. (5) Personal and professional growth occurs when doctors are empowered to make changes to their practice. (6) Cultures that stigmatise help-seeking undermine support, while those that model vulnerability and normalise support enhance the likelihood of positive outcomes. Conclusions Our guide provides step-by-step advice to identify key actions for those delivering professional support . Since the realist approach identifies principles and causal explanations, the findings are likely transferable to other settings/countries.